Crosstalk between m6A and coding/non-coding RNA in cancer and detection methods of m6A modification residues

Introduction

As is well known, RNAs play an essential role in the translation process, gene regulation, and environmental interactions [1]. Chemical modification is a highly specific and effective method for regulating the functions of biological macromolecules. These macromolecules can be covalently modified after synthesis, such as RNA, DNA, protein, lipids, carbohydrates, and polysaccharides [2]. RNA modification not only has dynamic reversibility but can also be regulated by a wide range of factors, which has led to the emergence of the term “RNA epitranscriptome” and has become increasingly popular in recent years [3]. Recently, more than 100 RNA modification types on bases or ribose have been discovered within all types of RNA, including ribosome RNA (rRNA), transfer RNA (tRNA), messenger RNA (mRNA) and non-coding RNA (ncRNA), which have been confirmed to be involved in many diseases and bio-processes [2, 4, 5]. For example, various RNA modifications in mRNA like N6-methyladenosine (m6A) [6], N4-acetylcysteine (ac4C) [7], N7-methyl guanidine (m7G) [8], 5-methylcytidine (m5C) [9] and N1-methyladenosine (m1A) [10] (Figure 1), are conducive to RNA metabolism steps including splicing, translocation, transcript stability and translation in eukaryotic cells, especially m6A [11]. NAT10 (RNA acetyltransferase)-mediated ac4C can promote mRNA’s stability by extending the mRNA’s half-life in Hela cells [12]. In addition, METTL1-dependent m7G on pre-let-7 regulates pre-let-7 and let-7 expression levels and lung cancer cell migration [13]. Interestingly, even when targeting the same type of methylation, the sets of methyltransferases and demethylases, acting as writers and erasers respectively, can vary across different types of RNA species [14].

Figure 1. Diverse RNA modification patterns. m7G, N7-methylguanosine; m6A, N6-methyladenosine; ac4C, N4-acetylcytidine; m1A, N1-methyladenosine; m5C, N5-methylcytidine.

This review will summarize the physiological function of m6A or m6A regulators and focus on the interplay of m6A and protein-coding RNA, and ncRNAs (miRNA, circRNA, lncRNA) in various cancers. Finally, we will list the experimental detection and prediction methods of m6A modification residues and summarize m6A-related databases.

Functional mechanism of m6A modification

The enzymes that deposit, remove and bind to RNA modifications are writers, erasers, and readers [3]. Intriguingly, m6A modifications are reversible and dynamic, which is mediated by catalyzing writers and erasers (Table 1). Generally, adenosine methylation occurs preferentially within different consensus sequences. The METTL3/14 complex prefers RRACH (R = G or A; H = A, C or U) in coding regions and 3′UTRs or consensus motif DRACH (D = A, G or U). The crystal structure suggests that another writer, METTL16, prefers a UAC (m6A) GAGAA motif in the bulge of a stem-loop structured RNA (Figure 2, Table 1) [11, 15–17].

Table 1. Biological functions of m6A regulators in RNA metabolism.

Type	Regulators	Location	Functions	References
m6A writers	METTL3	Nucleus	Installs m6A on mRNAs as well as lncRNAs and mediate RNA translation	[11, 183]
	METTL14	Nucleus	Assists METTL3 for m6A deposition and strengthens METTL3 activity	[11, 15, 184]
	METTL16	Nucleus	Installs m6A in U6 snRNA	[26]
	WTAP	Nucleus	Mediates METTL3-METTL14 to the nuclear speckle	[21]
	VIRMA	Nucleus	Guides the writers to RNA specific region	[23]
	RBM15	Nucleus	Binds to m6A complex and recruit it to special RNA site	[22]
	ZC3H13	Nucleus	Assists WTAP location to Nito	[185]
m6A eraser	FTO	Nucleus	Removes m6A modification and mediates alternative splicing	[27]
	ALKBH5	Nucleus	Removes m6A modification	[29]
m6A readers	YTHDF1	Cytoplasm	Promotes RNA translation	[20]
	YTHDF2	Cytoplasm	Reduces RNA stability and facilitates RNA degradation	[36]
	YTHDF3	Cytoplasm	Mediates the translation with YTHDF1 and strengthens RNA decay with YTHDF2	[39]
	YTHDC1	Nucleus	Promotes RNA alternative splicing and regulate nuclear mRNA transport	[35]
	YTHDC2	Cytoplasm	Augments RNA translation	[186]
	HNRNPA2B1	Nucleus	Promotes primary microRNA processing and regulates alternative splicing	[42]
	HNRNPC	Nucleus	Participates in pre-mRNA splicing	[43, 187, 188]
	HNRNPG	Nucleus	Mediates pre-mRNA splicing	[187]
	IGF2BP1	Cytoplasm	Enhances mRNA stability and translation	[47]
	IGF2BP2	Cytoplasm	Enhances mRNA stability and translation	[47]
	IGF2BP3	Cytoplasm	Enhances mRNA stability and translation	[47]

Figure 2. Overview of m6A-mediated RNA metabolism. “Writers” install m6A on coding RNAs and non-coding RNAs, whereas m6A can be reversibly removed by “Erasers”. Diverse m6A “Readers” determine the fate of m6A-modified RNAs involved in the structural switch, splicing, translocation, translation, and decay. MTC, methyltransferase complex.

Writers

The m6A modifications can be catalyzed by m6A writers (m6A methyltransferases). Typically discovered writers include methyltransferase-like 3/14/16 (METTL3/14/16) and other cofactors such as RNA binding motif protein 15/15B (RBM15/15B), wt1-associated protein (WTAP) and vir-like m6A methyltransferase-associated protein (VIRMA), which form the methyltransferase complex (MTC) [11]. Among them, METTL3 is a core component with methyltransferase activity by transferring the methyl from S-adenosyl methionine (SAM) into the N6 site of adenosine [11]. In comparison, METTL14 can impact the stability and methyltransferase activity [18] of the METTL3 complex and recognize the histone modification mark H3K36me3 to regulate the selection of modification sites on RNA [19, 20]. WTAP, known as cofactors and regulatory components of the complex, can guide METTL3/14-RNA binding and locate into nuclear speckles [21]. And RBM15 and its paralog RBM15B show the WTAP-dependent function of recruiting MTC into specific methylate RNA sites [22]. VIRMA is considered an essential part of MTC, showing a similar function as RBM15 [23]. Loss of METTL3 will induce endothelial cells to fail to transform into hematopoietic stem/progenitor cells in zebrafish and mouse embryos [24]. In addition, specific deletion of METTL3 in the central nervous system can lead to severe motif motor dysfunction during lactation and death in mice [25].

Other atypical methyltransferases such as METTL16, ZCCHC4, and METTL5 are discovered and indispensable for m6A [5]. For example, METTL16, a conserved U6 snRNA methyltransferase, regulates the intracellular SAM contents by methylating the SAM synthetase gene MAT2A and participating in the RNA splicing process [26]. Su and colleagues found that METTL16 had the most crucial effect on the survival of tumor cells among all METTL protein families. METTL16 plays a more critical role in almost all tumor cells as an oncogenic gene compared to METTL3 and METTL14. In the nucleus, METTL16 catalyzed the m6A modification of mRNA, especially of nascent mRNA. In the cytoplasm, METTL16 promoted the assembly of 80S ribosomes by directly binding with eIF3a/b and rRNAs, thus improving the translation efficiency of proteins and thus promoting the development of tumors (such as liver cancer) [18]. These results suggest that targeting METTL16, primarily the Mtase domain, may be a potential new tumor therapy strategy.

Erasers

m6A erasers account for the reverse demethylation of modified m6A base, which belongs to the Fe(II)/α-KG-dependent dioxygenase AlkB family: α-ketoglutarate-dependent dioxygenase AlkB homolog 5 (ALKBH5) and the mass-and obesity-associated protein (FTO) [5, 11]. Although FTO is the first identified demethylating enzyme associated with adipogenesis, the following evidence indicates that FTO preferentially demethylates 2’-O-dimethyladenosine (m6Am) [27]. More recently, FTO was revealed to demethylate N1-methyladenosine (m1A) in tRNA [28]. ALKBH5, considered as a secondly discovered m6A demethylase enzyme, has the conservatively catalytic domain to recognize and demethylate m6A modification sites regardless of single or double-stranded RNA [5]. ALKBH5 knockdown in mice affects nascent mRNA synthesis and the splicing rate in mice and humans, respectively [29, 30].

Readers

m6A modification can be recognized by the translation initiation factor eukaryotic initiation factor 3 (eIF3), heterogeneous nuclear ribonucleoproteins (HNRNPs), insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs), and proteins containing the YT521B homology (YTH) domain. In addition, specific m6A readers may mediate different physiological processes, such as immune response and biological rhythm, and participate in RNA metabolism steps such as RNA degradation and translation by binding the m6A modification site directly [11, 31, 32].

Generally, the YTH domain family is composed of YTH domain family protein 1-3 (YTHDF1-3, DF family) and YTH domain-containing protein 1-2 (YTHDC1-2, DC family) in mammalian cells. YTHDC1 belongs to nuclear m6A readers functioning on selectively binding m6A-containing precursor RNAs, while other YTH family members, including YTHDF1, YTHDF2, YTHDF3, and YTHDC2, identified as cytoplasmic m6A readers, regulate the mature mRNAs containing m6A [33].

YTHDC1 also can recognize m6A on XIST and enhance XIST-mediated X chromosome silencing [22]. YTHDC1, in Hela cells, recognizes m6A to form mRNA-protein complex and further interacts with RNA export factor 1 (NXF1) and serine/arginine-rich splicing factor 3 (SRSF3) to facilitate the m6A-methylated mRNAs nuclear export [34]. In addition to the function of silencing and nuclear export, YTHDC1 promotes exon inclusion or exon skipping via selectively recruiting or inhibiting different splicing factors, such as serine-arginine repeat protein. In addition, YTHDC1 recruits competitive RNA splicing factors SRSF3 and blocks serine/arginine-rich splicing factor 10 (SRSF10) from binding to mRNA to regulate exon inclusion and exon skipping, respectively [35].

YTHDC2 preferentially binds m6A within a precisely consensus motif and promotes the translation efficiency of mRNAs. YTHDC2 contains multiple functional elements, such as ankyrin repeats and the R3H domain, and these unique features endow YTHDC2 with many functions, including regulatory effects on RNA binding and structure and recruitment of or binding with other protein complex members [33]. YTHDF1, in Hela cells, can bind to mRNA stop codons and m6A near the 3′UTR region, and augment translation efficiency by interacting with eukaryotic initiation Factor 3 (eIF3) in the 48S translation initiation complex rather than by the m7G-cap-dependent manner [20].

YTHDF2 acts as an m6A reader inducing mRNA degradation [36]. YTHDF2 decodes m6A on more than 2000 mRNAs in HeLa cells. And YTHDF2 knockout can cause the abundance of these mRNAs to increase significantly, suggesting that YTHDF2 is essential for m6A-modified mRNAs [36]. Furthermore, the stability of mRNAs regulated by YTHDF2 positively correlates with the degree of polyadenylation at its 3’end. mRNAs combined with YTHDF2 generally exhibit shorter polyadenylic acid tails than other mRNAs. Typically, YTHDF2 first binds to m6A through the YTH domain, and then its N-terminal domain interacts with the SH (superfamily homolog) domain of CNOT1 and recruits the CCR4/CAF/NOT complex to perform deadenylation [37]. Intriguingly, YTHDF2 is thought to co-localize with both decapping and deadenylation enzyme complexes under normal conditions and directs its target RNAs to processing bodies [37]. However, recent studies showed that almost no significant mRNA degradation events were observed in the p-body, indicating the importance and significance of YTHDF2 in directing the process of RNAs into p-body that still needs to be considered and explored [38]. YTHDF2 can also enhance the expression level of pro-inflammatory cytokines by promoting the degradation of KDM6B, known as the repressive mark H3K27me3 demethylase. Meanwhile, the repressive mark H3K27me3 can inhibit the methylation process on adenosine during the transcription process. KDM6B recruits m6A methyltransferase to remove the H3K27me3 modification near the target gene and promotes the m6A modification on the newly transcribed mRNA, suggesting that complex interactions of m6A modification and histone modification exist and need to be studied [19].

YTHDF3, together with YTHDF1, guides the m6A modified transcript to be combined with YTHDF2 to direct the target RNA into RNA degradation steps. In addition, YTHDF3 could mediate mRNA decay by interacting with YTHDF2. YTHDF3 could cooperate with YTHDF3 to regulate mRNA translation; however, it could not function directly [39]. Moreover, YTHDF3 deficiency will reduce the binding ability of YTHDF1 and YTHDF2 to the target RNA, while YTHDF1 or YTHDF2 loss reduces the amount of RNA that YTHDF3 binds, suggesting that YTHDF3 could indirectly improve m6A-dependent translation efficiency by enhancing the binding ability for YTHDF1 and its target RNAs. Intriguingly, the translation process of circRNA with m6A modification does not depend on YTHDF1 at all, but YTHDF3 is required. Notably, YTHDF3 recruits eIF4G2 that directly binds to internal ribosome entry sites (IRES) to initiate the translation process independent of eIF4E [40, 41].

HNRNP family members, a well-known RNA-binding protein family, involved in m6A modification, consist of heterogeneous nuclear ribonucleoproteins A2/B1 (HNRNPA2B1), heterogeneous nuclear ribonucleoproteins G (HNRNPG) and heterogeneous nuclear ribonucleoproteins C (HNRNPC). Controversially, is HNRNPA2B1 an m6A reader or not? One study showed that HNRNPA2B1 could directly bind m6A and regulate alternative splicing events by cooperating with METTL3 and primary microRNA processing via interacting with pri-miRNA microprocessor complex component DGCR8. In contrast, a structure-based study revealed an “m6A switch” mechanism rather than specific m6A binding mediated by HNRNPA2B1 [42]. Another two HNRNP family members, HNRNPC and HNRNPG, can regulate the processing of m6A-containing RNA transcripts. HNRNPC also participates in the pre-mRNAs processing steps [43]. However, they do not bind to m6A directly, suggesting that HNRNPC and HNRNPG can bind to the transcripts via RNA structure alternations determined by m6A [44].

eIF3, considered as an m6A reader, recruits 43S protein complex to initiate the translation steps for mRNAs containing 5′UTR m6A without cap-binding factor eIF4E, that is, eIF3 functions in a cap-dependent manner. However, the exact mechanism of eIF3 for m6A recognition is not yet clearly understood. It may rely on the sequence motif like YTH proteins and adjacent RNA structure [45, 46].

IGF2BPs are the conserved m6A-binding proteins, whose RNA-binding domains are composed of RNA recognition motif (RRM) domains and K homology (KH) domains. IGF2BP family members, IGF2BP1, IGF2BP2, and IGF2BP3, can promote the stability and increase the translation efficiency of m6A-modified mRNAs. Additionally, the mRNA stabilization regulated by IGF2BPs may be enhanced by recruiting cofactors such as matrin 3 (MATR3) and ELAV-like RNA binding protein 1 (ELAVL1) [47].

m6A writers, erasers, and readers in cancers

Growing studies revealed that the global abundance of m6A and expression level of m6A regulators often show aberrance across various cancers and are associated with cancer initiation, progression, metastasis, relapse, and therapy [48–50]. Human HCC showed a higher abundance of m6A and augmented gene expression levels when YTHDC2 was knocked down, whereas the global abundance of m6A was reduced significantly in human bladder cancer [51]. This contradiction suggests that research on m6A needs to be more detailed and context dependent. Thus, a comprehensive understanding of m6A regulators may account for better prevention and treatment (Figure 3, Table 2).

Figure 3. m6A regulates coding RNAs in cancers. Generally, m6A promotes cancer via the stabilization or translation of oncogenes and the degradation of tumor suppressor genes. Adversely, m6A suppresses cancer via the stabilization or translation of tumor suppressor genes, the degradation of the oncogene. Abbreviations: GBM: glioblastoma; GC: gastric cancer; HB: hepatoblastoma; OS: osteosarcoma; BCA: bladder cancer; LCA: lung cancer; HCC: hepatocellular cancer; PCA: prostate cancer; CRC: colorectal cancer; BC: breast cancer; LUSC: lung squamous cell carcinoma; MEL: melanoma; OM: ocular melanoma; RCC: renal cell carcinoma; EC: endometrial carcinoma.

Table 2. Aberrant m6A regulators and its potential mRNA targets in cancers.

m6A regulator	Cancer type	Regulators Roles	Target	Regulators functions	References
METTL3-METTL14	Acute Myelocytic Leukemia	Oncogene	MYC, SP1, SP2, BCL2, PTEN	↑Proliferation	[189]
	Lung cancer	Oncogene	EGFR, BRD4, JUNB	↑Invasion, ↑Proliferation	[59, 60, 190]
	Hepatocellular carcinoma	Oncogene	SOCS2, SNAIL	↑Proliferation, ↑Migration	[54, 191]
	Endometrial cancer	Tumor suppressor gene	PHLPP2	↓Proliferation, ↓Migration	[192]
	Pancreatic cancer	Tumor suppressor gene	PHLPP2	↓Proliferation	[64]
	Pancreatic cancer	Oncogene	PERP	↑Growth, ↑Metastasis	[193]
	Glioblastoma	Oncogene	SOX2, SRSF, ADAR1	↑self-renewal, ↑Proliferation	[52, 194, 195]
	Glioblastoma	Tumor suppressor gene	ADAM19, KLF4, BRCA2, CDKN2A	↓Growth, ↓self-renewal	[63]
	Ovarian tumor	Oncogene	AXL	↑Invasion	[196]
	Bladder cancer	Oncogene	AFF4, IKBKB, CDCP1, MYC, ALF4	↑Growth	[57, 58, 197]
	Breast cancer	Oncogene	MYC, KLF4, HBXIP	↑Proliferation, ↑Migration	[198, 199]
	Breast cancer	Tumor suppressor gene	NOTCH1	↓Proliferation	[152]
	Prostate cancer	Oncogene	LEF1/LHPP	↑Proliferation, ↑Migration	[200, 201]
	Colorectal cancer	Tumor suppressor gene	ARRDC4	↓Invasion, ↓Migration	[202]
	Colorectal cancer	Oncogene	CCNE1	↑Proliferation	[56]
	Thyroid carcinoma	Oncogene	TCF1	↑Proliferation	[203]
	Gastric cancer	Oncogene	BATF2, HDGF	↑Proliferation	[53, 204]
	Kidney cancer	Tumor suppressor gene	P2RX6	↓Invasion, ↓Migration	[205]
	Hepatoblastoma	Oncogene	CTNNB1	↑Proliferation	[55]
	Nasopharynegal carcinoma	Oncogene	ZNF750	↑Growth	[206]
WTAP	Hepatocellular carcinoma	Oncogene	ETS1	↑Proliferation	[67]
	Osteosarcoma	Oncogene	HMBOX1	↑Tumorigenicity	[207]
RBM15	Laryngeal squamous cell carcinoma	Oncogene	TMBIM6	↑Proliferation	[208]
FTO	Cutaneous melanoma	Oncogene	PDCD, CXCR4, SOX10	↑Tumorigenicity	[74]
	Acute Myelocytic Leukemia	Oncogene	ASB2, RARA, MYC, CEBPA	↑Proliferation	[71]
	Clear cell renal cell carcinoma	Tumor suppressor gene	PGC-1α	↓Proliferation	[209]
	Cervical cancer	Oncogene	β-catenin	↑Development	[210]
	Lung cancer	Oncogene	MZF1	↑Proliferation, ↑Invasion	[211]
	Hepatocellular carcinoma	Oncogene	PKM2	↑Tumorigenicity	[212]
	Breast cancer	Oncogene	BNIP3	↑Growth	[73]
ALKBH5	Glioblastoma	Oncogene	FOXM1	↑Tumorigenicity	[80]
	Acute Myelocytic Leukemia	Oncogene	TACC3, AXL	↑Self-renewal	[81, 213]
	Ovarian tumor	Oncogene	NANOG	↑Proliferation	[214]
	Pancreatic cancer	Tumor suppressor gene	PER1	↓Proliferation	[215]
	Lung cancer	Oncogene	UBE2C, TIMP3	↑Proliferation	[216, 217]
	Hepatocellular carcinoma	Tumor suppressor gene	LYPD1	↓Proliferation	[83]
YTHDC2	Lung adenocarcinoma	Tumor suppressor gene	SLC7A11	↓Tumorigenicity	[218]
	Bladder cancer	Oncogene	CDCP1	↑Growth	[197]
YTHDF1	Colorectal cancer	Oncogene	Wnt/β-catenin	↑Tumorigenicity	[87]
	Hepatocellular carcinoma	Oncogene	FZD5	↑Proliferation	[84]
	Non-small-cell lung cancer	Oncogene	CDK2, CKD4	↑Proliferation	[86]
	Gastric cancer	Oncogene	FZD7	↑Tumorigenicity	[219]
	Endometrial cancer	Tumor suppressor gene	PHLPP2	↓Proliferation	[192]
	Ovarian tumor	Oncogene	EIF3C	↑Proliferation, ↑Migration	[220]
	Ocular melanoma	Tumor suppressor gene	HINT2	↓Proliferation	[91]
YTHDF2	Glioblastoma	Oncogene	MYC/UBXN1	↑Proliferation, ↑Self-renewal	[221, 222]
	Ovarian cancer	Oncogene	BMF	↓Apoptosis	[223]
	Hepatocellular carcinoma	Oncogene	OCT4	↑Growth	[224]
	Hepatocellular carcinoma	Tumor suppressor gene	EGFR	↓Proliferation, ↓Growth	[94]
	Ovarian tumor	Oncogene	FOXK1, PDLIM7	↑Growth	[225]
	Liver cancer/ovarian cancer/lung cancer	Oncogene	E2F1	↑Proliferation	[226]
IGF2BP1	Colorectal cancer	Oncogene	SOX2, SEC62	↑Tumorigenicity, ↑Proliferation	[227, 228]
	Hepatocellular carcinoma	Oncogene	SRF/FEN1	↑Growth	[225, 226]
IGF2BP2	Clear cell renal cell carcinoma	Oncogene	CDK4	↑Proliferation	[229]
	Colon cancer	Oncogene	CCND1	↑Proliferation	[230]
IGF2BP3	Melanoma	Oncogene	MMP2	↑Proliferation, ↑Migration	[231]
	Multiple myeloma	Oncogene	ILF3	↑Growth	[232]

The interplay of m6A and miRNAs in cancers

Usually, miRNAs can regulate gene expression by forming RISC (RNA-induced silencing complex) at the post-transcriptional level with a distributed length of 21–25nt. And miRNAs bind to the 3′UTR of regulated genes, leading to the degradation or translational inhibition of target RNAs. In recent years, growing studies have shown that m6A mediation occurs on miRNAs that affect oncogenes or tumor suppressor genes to impact the tumor process [105, 106] (Figure 4).

Figure 4. Crosstalk of m6A and miRNAs. m6A can modulate miRNA processing, maturating, or pre-miRNA splicing via “Writers” or “Readers” to inhibit or promote cancers. miRNAs regulate m6A regulators by sponging to affect m6A modification, suppressing or promoting cancers. Abbreviations: OV: ovarian cancer; BCA: bladder cancer; CRC: colorectal cancer; HCC: hepatocellular cancer; PDAC: pancreatic ductal adenocarcinoma; BC: breast cancer; GBM: glioblastoma; NSCLC: non-small cell lung cancer.

M6A methylation affects miRNA processing. For example, miRNA biogenesis involves the following three steps, miRNAs are transcribed as long primary miRNAs (pri-miRNAs) in the nucleus, and these pri-miRNAs are subsequently processed into precursor miRNAs (pre-miRNAs) by a microprocessor complex composed of DGCR8 and DROSHA, and then cleaved by Dicer into mature single-strand miRNAs in the cytoplasm [105].

Intriguingly, the miRNAs biogenesis steps can be affected by m6A regulators in an m6A-dependent manner. METTL3 and HNRNPA2B1 regulate m6A modification on pri-miRNAs to promote the recognition ability of DGCR8 [42, 107]. METTL3 interacts with DGCR8 to promote miR-221/222 maturation which can promote cancer cell proliferation and growth by reducing PTEN expression in bladder cancer cells [108]. In addition, METTL3 also enhances the CRC cells’ metastasis process by facilitating miR-1246 biogenesis and functioning on the miR-1246/SPRED2/MARK signaling pathway [109]. Cigarette smoke condensate promotes the growth of pancreatic ductal adenocarcinoma cells by inducing the maturation of METTL3-mediated m6A-modified pri-miR-25-3p [64]. M6A impacts the maturation of pre-miRNAs and the pre-miRNAs to influence cancer progression. For example, miR-143-3p can be cleaved from pre-miR-143-3p under m6A-modified conditions, playing an essential role in NSCLC with brain metastasis by regulating vasohibin-1 (VASH1) [110]. Like METTL3, METTL14 can also affect miRNA maturation in an m6A-dependent manner to promote or suppress cancer progression. For instance, METTL14 enhances the identification and binding of DGCR8 to facilitate the maturation of pri-miR-126 whose products miR-126 can inhibit HCC cell migration and invasion [111]. Another study showed that METTL14 suppressed CRC progression by promoting the m6A-dependent maturation of miR-375, which functions on YAP1 and SP1 to suppress proliferation and migration [112]. Moreover, m6A reader HNRNPC induces higher expression of miR-21, leading to lower expression of PDCD4 and active migratory and invasive activity in glioblastoma metastasis [113] (Table 3).

Table 3. m6A modulates miRNA processing in cancers.

m6A regulators	Cancer type	Mechanism	Regulators functions	References
METTL3	Bladder cancer	Promotes the processing of miR-221/222 with DGCR8	↑Proliferation	[108]
METTL3	Colorectal cancer	Promotes the processing of miR-1246 with DGCR8	↑Migration, ↑Invasion	[109]
METTL3	Pancreatic ductal adenocarcinoma	Promotes miR-25-3p maturation	↑Migration, ↑Invasion	[64]
METTL3	Non-small cell lung cancer	Promotes splicing of pre-miR-143-3p	↑Invasion	[110]
METTL3	Ovarian cancer	Promotes miR-126-5p maturation	↑Migration, ↑Invasion	[233]
METTL14	Hepatocellular carcinoma	Promotes the processing of miR-126 with DGCR8	↓Migration, ↓Invasion	[111]
METTL14	Colorectal cancer	Promotes the processing of miR-375 with DGCR8	↓Migration, ↓Growth	[112]
METTL3	Breast cancer	Promotes miR-221-3p maturation	↑Adriamycin resistance	[234]
HNRNPC	Glioblastoma	Promotes miR-21 maturation by binding to pri-miR-21	↑Migration, ↑Invasion	[64]
IGF2BP1	Hepatocellular carcinoma	Impairs the miRNA-directed decay of the SRF mRNA	↑Proliferation	[225]

However, m6A may affect miRNA biogenesis or stability. ALKBH5 interacts with DDX3, which modulates the demethylation of mRNAs by regulating miRNAs [114]. Significantly increased HNONPA2B1 in endocrine-resistant breast cancer reduces the sensitivity to hydro tamoxifen, which is mediated by regulated miRNAs such as miR-29-3p and miR-1268a [115].

Mature miRNAs regulate m6A regulators in cancers. Interestingly, m6A affects the synthesis and function of miRNA directly and impacts the mRNA indirectly mediated by miRNA. IGF2BP2 maintains RAF-1 mRNA stability by obstructing miRNA-mediated degradation, leading to cancer cell proliferation in CRC [116]. Another study showed that miR-1246 suppresses anti-oncogene SPRED2 to induce cancer cell migration and invasion. Mechanistically, METTL3 methylated pri-miR-1246 and facilitated the maturation of pri-miR-1246 [109]. In addition to the above, the m6A regulators may be regulated by miRNA. For example, tumor-suppressive miR-34a suppresses potential oncogenic IGF2BP3 to inhibit cell proliferation and invasion [117]. One other study showed that miR-145 negatively regulated YTHDF2 in HCC cells [118]. However, the mechanism of miRNA functioning in m6A modification remains unclear (Table 4).

Table 4. miRNA regulates m6A regulators via sponging in cancers.

miRNA	m6A regulators	Cancer type	miRNA functions	References
miR-4429	METTL3	Gastric cancer	↓Proliferation, ↑Apoptosis	[235]
miR-33a	METTL3	Non-small cell lung cancer	↓Proliferation	[236]
Let-7g	METTL3	Breast cancer	↓Proliferation	[198]
miR-600	METTL3	Non-small cell lung cancer	↓Migration, ↑Apoptosis	[237]
miR-186	METTL3	Hepatocellular carcinoma	↓Migration, ↓Invasion	[238]
miR-96	FTO	Colorectal cancer	↑Migration, ↑Invasion	[239]
miR-1266	FTO	Colorectal cancer	↓Proliferation	[240]
miR-744-5p	HNRNPC	Ovarian cancer	↑Apoptosis	[241]
miR-346	YTHDF1	Glioma	↓Proliferation	[242]
miR-145	YTHDF2	Colorectal cancer/Hepatocellular carcinoma	↓Proliferation	[118]

Collectively, m6A is a critical regulator of miRNA at multiple levels, such as maturation, and reverse regulation for m6A regulators by miRNAs is also vital. Therefore, it is essential to investigate the diverse interactions of m6A and miRNAs directly or indirectly.

The interplay of m6A and lncRNAs in cancers

lncRNA, a subgroup of ncRNAs with a length of over 200 nucleotides, can be modified by m6A modification. Researchers are increasingly finding that the interplay of m6A or m6A regulators and lncRNAs could participate in cancer cell proliferation, migration, invasion, or drug resistance. On the one hand, m6A regulators write or recognize the modifiable site lncRNAs which provides to regulate the structure conformation as a structure switch, thereby impacting the RNA-DNA binding ability. On the other hand, lncRNAs serve as endogenous competitive RNAs (ceRNAs) to regulate m6A regulators or directly interact with m6A regulators [119–122] (Figure 5, Tables 5, and 6).

Figure 5. Interplays of m6A and lncRNAs. m6A can modulate the stability, degradation, or accumulation of lncRNAs to regulate cancer initiation, progression, and therapy. Conversely, lncRNAs can serve as ceRNAs to regulate m6A regulators via sponging miRNAs or interact directly with m6A regulators to facilitate or inhibit cancer. Abbreviations: BC: breast cancer; HCC: hepatocellular carcinoma; PCA: prostate cancer; LC: lung cancer; GC: gastric cancer; PC: pancreatic cancer; OS: osteosarcoma; CRC: colorectal cancer; RCC: renal cell carcinoma; PTC: papillary thyroid cancer; ESCC: esophageal squamous cell carcinoma; GBM: glioblastoma.

Table 5. m6A modification regulates lncRNA in cancers.

m6A regulators	m6A function	LncRNA	Cancer type	Regulator role	LncRNA role	Mechanism	Regulator functions	References
METTL3	writer	MALAT1	Breast cancer	Oncogene	Oncogene	Promotes RNA stability of MALAT1	↑Migration, ↑Invasion	[124]
METTL14	writer	XIST	Colorectal carcinoma	Tumor suppressor gene	Oncogene	Promote degradation of XIST	↓Migration, ↓Invasion	[123]
METTL3	writer	NEAT1	Chronic myeloid leukemia	Oncogene	Oncogene	Induces aberrant expression of NEAT1	↑Migration, ↑Invasion	[243]
ALKBH5	eraser	PVT1	Osteosarcoma	Oncogene	Oncogene	Demethylates PVT1 and enhances its expression	↑Proliferation	[130]
METTL3	writer	LINC00958	Hepatocellular carcinoma/Breast cancer	Oncogene	Oncogene	Promotes the stability of LINC00958	↑Migration, ↑Invasion	[125, 244]
METTL3	writer	FAM225A	Nasopharyngeal carcinogenesis	Oncogene	Oncogene	Promotes the stability of FAM225A	↑Tumorigenesis, ↑Metastasis	[126]
METTL3	writer	RP11	Colorectal carcinoma	Oncogene	Oncogene	Increases the accumulation of RP11	↑Migration, ↑Invasion	[127]
ALHBK5	eraser	KCNK15-AS1	Pancreatic cancer	Tumor suppressor gene	Oncogene	Enhances expression of KCNK15-AS1	↓Migration, ↓Invasion	[131]
FTO	eraser	LINC00022	Esophageal squamous cell carcinoma	Oncogene	Oncogene	Inhibits the decay of LINC00022	↑Proliferation	[132]
IGF2BP2	reader	DANCR	Pancreatic cancer	Oncogene	Oncogene	Promotes the stability of DANCR	↑Proliferation	[133]
METTL3	writer	ABHD11-AS1	Non-small cell lung cancer	Oncogene	Oncogene	Promotes the stability of ABHD11-AS1	↑Proliferation, ↑Warburg effect	[128]
YTHDF3	reader	GAS5	Colorectal carcinoma	Oncogene	Tumor suppressor gene	Promotes the degradation of GAS5	↑Progression	[97]
METTL14	writer	NEAT1	Clear cell renal cell carcinoma	Tumor suppressor gene	Oncogene	Promotes degradation of NEAT1_1	↓Migration, ↓Invasion	[245]
ALKBH5	eraser	NEAT1	Colon cancer, gastric cancer	Oncogene	Oncogene	Promotes demethylation of NEAT1	↑Migration, ↑Proliferation	[129, 246]
METTL3, METTL14	writer	LNCAROD	Headneck squamous cell carcinoma	Oncogene	Oncogene	Promotes the stability of LNCAROD	↑Proliferation	[247]
METTL3	writer	FOXD2-AS1	Cervical cancer	Oncogene	Oncogene	Enhances the stability of FOXD2-AS1	↑Tumorigenesis	[248]
METTL3	writer	THAP7-AS1	Gastric cancer	Oncogene	Oncogene	Enhances the stability of THAP7-AS1	↑Migration, ↑Invasion	[249]
METTL3	writer	MEG3	Hepatocellular carcinoma	Oncogene	Tumor suppressor gene	Promotes degradation of MEG3	↑Migration, ↑Invasion	[250]
METTL3	writer	PCAT6	Prostate cancer	Oncogene	Oncogene	Enhances the stability of PCAT6	↑Metastasis	[251]
METTL3	writer	LCAT3	Lung cancer	Oncogene	Oncogene	Enhances the stability of LCAT3	↑Migration, ↑Invasion	[252]
METTL14	writer	Lnc-LSG1	Clear cell renal cell carcinoma	Tumor suppressor gene	Oncogene	Blocks the interaction of Lnc-LSG1 and ESPR2	↓Migration, ↓Invasion	[253]
METTL14	writer	OIP5-AS1	Papillary thyroid cancer	Oncogene	Tumor suppressor gene	Inhibits OIP5-AS1 expression	↑Migration, ↑Invasion	[254]

Table 6. LncRNA modulates m6A regulators in cancer.

LncRNA	m6A regulators	Type	Cancer type	LncRNA role	Regulator role	Mechanism	References
LINC00470	METTL3	writer	Gastric cancer	Oncogene	Oncogene	LINC00470 promotes METTL3-mediated PTEN mRNA degradation	[136]
LINC00942	METTL14	writer	Breast cancer	Oncogene	Oncogene	Recruits METTL14 to mediate CXCR4 and CYP1B1 mRNA stability.	[255]
GATA3-AS	KIAA1429	writer	Hepatocellular carcinoma	Oncogene	Oncogene	Mediate interaction of KIAA1429 with GATA3 pre-mRNA to methylate and degrade GATA3 pre-mRNA	[70]
UTM2A-AS1	METTL3	writer	Lung adenocarcinoma	Oncogene	Oncogene	Regulates the miR-590-5p/METTL3 axis	[256]
LINC00240	METTL3	writer	Gastric cancer	Oncogene	Oncogene	Modulates miR-338-5p/METTL3 axis	[257]
BLACAT2	METTL3	writer	Gastric cancer	Oncogene	Oncogene	Modulates miR-193b-5p/METTL3	[258]
IFL3-AS1	METTL3	writer	Hepatocellular carcinoma	Oncogene	Oncogene	Inhibits the degradation of ILF3 mRNA	[259]
FOXM1-AS	ALKBH5	eraser	Glioblastoma	Oncogene	Oncogene	Promotes the interaction of ALKBH5 with FOXM1 to enhance demethylation of FOXM1	[80]
GAS5-AS1	ALKBH5	eraser	Cervical cancer	Tumor suppressor gene	Tumor suppressor gene	Interacts with ALKBH5 to demethylate GAS5 to promote tumor suppressor gene GAS5 stability	[260]
MALAT1	IGF2BP2	reader	Thyroid cancer	Oncogene	Oncogene	miR-204/IGF2BP2/m6A-MYC	[134]
LINRIS	IGF2BP2	reader	Colorectal cancer	Oncogene	Oncogene	LINRIS maintains the stability of IGF2BP2	[135]
KB-1980E6.3	IGF2BP1	reader	Breast cancer stem cells	Oncogene	Oncogene	Recruits IGF2BP1 to mediate c-Myc mRNA stability.	[137]
LINC00857	YTHDC1	reader	Colorectal cancer	Oncogene	Oncogene	Interacts with YTHDC1 to stabilize SLC7A5	[261]
LIN28B-AS1	IGF2BP1	reader	Hepatocellular carcinoma, lung adenocarcinoma	Oncogene	Oncogene	Activate LIN28B by interacting with IGF2BP1	[262]
miR503HG	HNRNPA2B1	reader	Hepatocellular carcinoma	Tumor suppressor gene	Oncogene	Promotes HNRNPA2B1 degradation	[263]
DMDRMR	IGF2BP3	reader	Clear cell renal cell carcinoma	Oncogene	Oncogene	Up-regulates m6A-modified CDK4 via interacting with IGF2BP3.	[264]
LINC01234	HNRNPA2B1	reader	Non-small-cell lung cancer	Oncogene	Oncogene	Facilitates the processing of pri-miR-106b	[265]

M6A regulates lncRNA to promote or suppress cancer progression. It has been shown that METTL3, METTL14, and RBM15 can mediate the silencing of lncRNA XIST in a YTHDF2-dependent m6A manner [22, 123]. As for oncogenes, one study showed that METTL3 up-regulated MALAT1 expression to facilitate breast cancer cell migration and invasion via the MALAT1/miR-26b/HMGA2 axis [124]. Moreover, m6A modification on LINC00958 mediated by METTL3 induces its higher expression with its RNA transcripts stabilizing, leading to HDGF up-regulation by sponging miR-3619-59 in HCC [125]. In nasopharyngeal carcinogenesis, METTL3 stabilized FAM225A via m6A modification and up-regulated FAM225A expression, thereby contributing to tumorigenesis and metastasis by sponging miR-590-3p/miR-1275 and up-regulating ITGB3 with the FAK/PI3K/AKT signaling pathway being activated [126]. METTL3 also increases RP11 accumulation via m6A modification in CRC, thus, preventing the degradation of ZEB1 by accelerating the degradation of E3 ligases SIAH1 and FBXO45 [127]. ABHD11-AS1, whose stability can be strengthened by METTL3, promotes NSCLC cell proliferation and the Warburg effect [128]. In addition to the writers, the m6A erasers and readers also regulated lncRNAs. For instance, overexpression of ALHBK5 in GC cells promotes invasion and metastasis by inhibiting NEAT1 methylation [129]. ALHBK5-mediated demethylation of lncRNA PVT1 promotes osteosarcoma cell proliferation [130]. ALHBK5 can also serve as a tumor suppressor. ALHBK5-mediated m6A demethylation on lncRNA KCNK15-AS1 can up-regulate KCNK15-AS1 expression to suppress pancreatic cancer cell migration and invasion while facilitating apoptosis [131]. Another eraser FTO inhibits the LINC00022 decay by decreasing its m6A modification, and LINC00022 promotes ESCC cell proliferation and cell-cycle progression by binding to p21 and promoting its degradation [132]. Regarding readers, IGF2BP2 stabilizes DANCR by recognizing DANCR modification, leading to the proliferation of pancreatic cancer cells [133] (Table 5).

Conversely, lncRNAs can affect m6A via regulating m6A regulators directly or indirectly. For example, MALAT1, considered an oncogene, acts as a ceRNA competitively binding to miR-204 to up-regulate IGF2BP2 expression and enhance MYC expression by m6A modification in thyroid cancer [134]. Moreover, LINRIS maintains the stability of IGF2BP2 by blocking ubiquitination, leading to CRC cell proliferation via MYC-mediated glycolysis [135]. Another study showed that LINC00470 interacted with METTL3 to facilitate PTEN mRNA degradation, thereby accelerating distal migration [136]. LncRNA KB-1980E6.3 is overexpressed and promotes breast cancer stem cell tumorigenesis and self-renewal via recruiting IGFBP1 and retaining c-Myc stability [137]. Furthermore, YTHDF3 accelerates the degradation of GAS5 to regulate YAP signaling and promote CRC progression [97]. Additionally, lncRNA ARHGAP5-AS1 can recruit METTL3 to stimulate ARHGAP5 mRNA m6A modification and stabilize ARHGAP5 mRNA, leading to chemoresistance in gastric cancer [138] (Table 6).

Overall, the interactions between m6A modification or m6A regulators and lncRNAs provide insight for a better understanding of cancer initiation, progression, and therapy.

The interplay of m6A and circRNAs in cancers

Circular RNAs, a group of ncRNAs characterized by covalently closed loop structures with neither 5′ to 3′ polarity nor polyadenylated tail, are more stable than linear RNAs due to their ring-closed structure [139]. Accumulating evidence shows the crosstalk between m6A modification or m6A regulators and circRNAs. Indeed, M6A modification modulates diverse functions of circRNAs, including expression, translation, location, and interaction with RNA or protein. Conversely, circRNAs can also affect m6A modification by regulating the m6A regulators, including writers, erasers, or readers. Surprisingly, aberrant circRNAs have been found and modified by m6A in diverse cancers. Exploring the crosstalk of m6A and circRNA is necessary for cancer therapy [119, 140] (Figure 6, Table 7).

Figure 6. Crosstalk between m6A and circRNAs. m6A facilitates the circulation, accumulation, translocation, translation, or degradation of circRNA to promote or suppress cancers via diverse cancer-associated signaling pathways or tumor-related oncogene/suppressors. On the contrary, circRNAs regulate m6A regulators like lncRNAs.

Table 7. The functions of m6A-modified circRNAs in cancers.

m6A regulators	m6A function	circRNA	Cancer type	Regulator role	circRNA role	Mechanism mediated by m6A	circRNA Functions	References
METTL3	writer	circNRIP1	Osteosarcoma	oncogene	oncogene	Promotes circNRIP1 expression	↑Proliferation, ↑Migration	[141]
ALKBH5/YTHDF3	eraser/reader	circ3823	Colorectal cancer	tumor suppressor gene	oncogene	Reduces circ3823 stability	↑Proliferation, ↑Metastasis, ↑Angiogenesis	[142]
METTL14/FTO	writer/eraser	circMETTL3	Breast cancer	oncogene/tumor suppressor gene	oncogene	Promotes/Reduces circMETTL3 expression	↑Proliferation, ↑Migration, ↑Invasion	[143]
YTHDC1	reader	circNSUN2	Colorectal cancer	oncogene	oncogene	Facilitates circNSUN2 cytoplasmic export and mediates HMGA2 stabilization	↑Metastasis	[102]
METTL3/YTHDC1	writer/reader	circHPS5	Hepatocellular carcinoma	oncogene	oncogene	Facilitates m6A-modified circHPS5 accumulation and cytoplasmic export	↑Proliferation, ↑Migration	[148]
METTL3/14	writer	circRNA-SORE	Hepatocellular carcinoma		sustains sorafenib resistance	Increases circRNA-SORE stability	Sustains sorafenib resistance	[266]
METTL3/YTHDC1	writer/reader	circ-ARL3	HBV- Hepatocellular carcinoma	oncogene	oncogene	Favors reverse splicing and biogenesis of circ-ARL3	↑Tumorigenesis	[149]
YTHDF2	reader	circASK1	lung adenocarcinoma		ameliorates gefitinib resistance	Increases endoribonucleolytic cleavage of m6A-modified circASK1	Ameliorate gefitinib resistance, ↑Apoptosis	[267]
METTL3/YTHDC1	writer/reader	circIGF2BP3	Non-small-cell lung cancer	oncogene	oncogene	Promotes circIGF2BP3 circularization	Facilitate tumor immune evasion	[150]
IGF2BP2	reader	circARHGAP12	cervical cancer		oncogene	Promotes circARHGAP12 stability	↑Progression	[144]
		circPVRL3	Gastric cancer		tumor suppressor gene	Promotes the circPVRL3 translation	↓Proliferation, ↓Migration	[151]
METTL3	writer	CircE7	cervical carcinoma		oncogene	Promotes CircE7 stability	↑Growth	[145]
METTL3	writer	circ1662	Colorectal cancer	oncogene	oncogene	Induces circ1662 expression and install m6A on it	↑Migration, ↑Invasion	[146]
METTL3	writer	circCUX1	Hypopharyngeal squamous cell carcinoma			Promotes circCUX1 stability and expression	Confers radio-resistance	[268]

m6A affects the location, biogenesis, stabilization, or translation of circRNAs, leading to cancer proliferation, migration, or invasion [140]. For example, in osteosarcoma, METTL3-mediated m6A modification on circNRIP1 can promote its expression to enhance cell proliferation and migration [141]. M6A-modified Circ3823 contributes to CRC cell proliferation and metastasis, which is regulated negatively by ALKBH5 and YTHDF3 [142]. Another study showed a similar result: high expression of circMETTL3 induced by METTL14-mediated m6A modification leads to breast cancer cell migration and invasion [143]. Other studies also reported that m6A could stabilize the circ-RNAs to impact cancer progressions, such as circARHGAP12 and CircE7 in cervical cancer [144, 145] and circ1662 in CRC [146]. As mentioned above, some studies showed that m6A regulated the translocation of circRNAs. In colorectal cancer, m6A mediation facilitates circNSUN2 cytoplasmic export and further mediates HMGA stabilization to promote cancer metastasis [147]. Another study reported that METTL3 could direct circHPS5 formation and METTL3-controlled m6A could also facilitate the circHPS5 accumulation and cytoplasmic export, indicating that m6A regulators may participate in the formation of circRNAs [148]. Oncogenic circ-ARL3, whose biogenesis is controlled by m6A modification, promotes tumorigenesis in HBV-HCC [149]. Furthermore, METTL3-mediated m6A modification promotes circIGF2BP3 circularization, facilitating NSCLC cells’ immune evasion. Although circRNAs are considered ncRNAs, some circRNAs have the potential to encode short peptides or proteins [150]. M6A promotes circPVRL3 translation, and circPVRL3 can inhibit GC cell migration and invasion [151]. Despite these initial investigations, the mechanisms underlying the functions of m6A-modified circRNAs still need to be explored, especially the translation process (Table 7).

circRNAs can regulate m6A modification on specific target genes by affecting the m6A regulator’s expression or functions. For instance, circNOTCH1 can competitively bind to METTL14 to regulate NOTCH1 mRNA modification, thereby controlling NOTCH1 expression [152]. CircRNAs can also interact with writers or erasers to control target gene m6A modification to further regulate the expression. CircARHGAP12 can interact with IGF2BP2 to accelerate the stability of FOXM1 mRNA, leading to cervical cancer progression [144]. Another study revealed that CircRAB11FIP1 promoted epithelial ovarian cancer cell proliferation and invasion via interacting with FTO to decrease the expression of ATG5 and ATG7 by demethylating their m6A modification [153]. And other circRNAs like circARHGAP12 in cervical cancer [144] and circ0008399 in bladder cancer [154] also perform similar functions. Like lncRNA, circRNAs can also act as ceRNAs to regulate the m6A regulators. For example, CircMAP2K4 and hsa_circ_0072309 enhance HCC and NSCLC cells proliferation and migration via the CircMAP2K4/miR-139-5p/YTHDF1 axis [155] and hsa_circ_0072309/miR-607/FTO axis [156], respectively. Importantly, circRNAs can only regulate m6A modification indirectly via m6A regulators rather than themselves directly (Table 8).

Table 8. CircRNA modulates m6A regulators in cancer.

circRNA	m6A regulators	m6A function	Cancer type	circRNA role	Mechanism	circRNA Functions	References
circARHGAP12	IGF2BP2	reader	cervical cancer	oncogene	Interacts with IGF2BP2 to accelerates the stability of FOXM1 mRNA	↑Progression	[144]
CircRAB11FIP1	FTO	eraser	epithelial ovarian cancer	oncogene	Interacts with FTO to decrease expression of ATG5 and ATG7	↑Proliferation, ↑Invasion	[153]
circ_KIAA1429	YTHDF3	reader	Hepatocellular carcinoma	oncogene	YTHDF3 enhanced Zeb1 mRNA stability	↑Proliferation, ↑Migration, ↑Invasion	[269]
CircMAP2K4	YTHDF1	reader	Hepatocellular carcinoma	oncogene	CircMAP2K4/miR-139-5p/YTHDF1 axis	↑Proliferation	[155]
circ0008399	WTAP	writer	bladder cancer	oncogene	Interacts with WTAP and increase TNFAIP3 stability	Reduce chemosensitivity to CDDP	[154]
circNOTCH1	METTL14	writer	Non-small-cell lung cancer	oncogene	Regulates NOTCH1 mRNA m6A modification by competing for METTL14 binding	↑Growth	[152]
hsa_circ_0072309	FTO	eraser	Non-small-cell lung cancer	oncogene	hsa_circ_0072309/miR-607/FTO axis	↑Tumorigenesis, ↑Invasion	[156]
CircMEG3	METTL3	writer	liver cancer	tumor suppressor gene	Inhibits the expression of METTL3 dependent on HULC	↓Growth	[270]
circNDUFB2	IGF2BPs	reader	Non-small-cell lung cancer	tumor suppressor gene	Destabilizes IGFBPs	↓Growth	[271]
CircPTPRA	IGF2BP1	reader	Bladder cancer	tumor suppressor gene	Blocks the recognition of m6A via interacting with IGF2BP1	↓Proliferation, ↓Migration, ↓Invasion	[272]

Author Contributions

Jun Chen supervised the project. Qingren Meng and Qian Zhou conceived and drafted the manuscript. Jun Chen and Heide Schatten edited the manuscript.

Conflicts of Interest

The authors declare no conflicts of interest related to this study.

Funding

Supported by the funds for the construction of key medical disciplines in Shenzhen (No. SZXK076).

References

• 1. Goodall GJ, Wickramasinghe VO. RNA in cancer. Nat Rev Cancer. 2021; 21:22–36. https://doi.org/10.1038/s41568-020-00306-0 [PubMed]
• 2. Roundtree IA, He C. RNA epigenetics--chemical messages for posttranscriptional gene regulation. Curr Opin Chem Biol. 2016; 30:46–51. https://doi.org/10.1016/j.cbpa.2015.10.024 [PubMed]
• 3. Barbieri I, Kouzarides T. Role of RNA modifications in cancer. Nat Rev Cancer. 2020; 20:303–22. https://doi.org/10.1038/s41568-020-0253-2 [PubMed]
• 4. Liang W, Lin Z, Du C, Qiu D, Zhang Q. mRNA modification orchestrates cancer stem cell fate decisions. Mol Cancer. 2020; 19:38. https://doi.org/10.1186/s12943-020-01166-w [PubMed]
• 5. Gu J, Zhan Y, Zhuo L, Zhang Q, Li G, Li Q, Qi S, Zhu J, Lv Q, Shen Y, Guo Y, Liu S, Xie T, Sui X. Biological functions of m⁶A methyltransferases. Cell Biosci. 2021; 11:15. https://doi.org/10.1186/s13578-020-00513-0 [PubMed]
• 6. Zhang H, Shi X, Huang T, Zhao X, Chen W, Gu N, Zhang R. Dynamic landscape and evolution of m6A methylation in human. Nucleic Acids Res. 2020; 48:6251–64. https://doi.org/10.1093/nar/gkaa347 [PubMed]
• 7. Sas-Chen A, Thomas JM, Matzov D, Taoka M, Nance KD, Nir R, Bryson KM, Shachar R, Liman GLS, Burkhart BW, Gamage ST, Nobe Y, Briney CA, et al. Dynamic RNA acetylation revealed by quantitative cross-evolutionary mapping. Nature. 2020; 583:638–43. https://doi.org/10.1038/s41586-020-2418-2 [PubMed]
• 8. Malbec L, Zhang T, Chen YS, Zhang Y, Sun BF, Shi BY, Zhao YL, Yang Y, Yang YG. Dynamic methylome of internal mRNA N⁷-methylguanosine and its regulatory role in translation. Cell Res. 2019; 29:927–41. https://doi.org/10.1038/s41422-019-0230-z [PubMed]
• 9. Shi H, Chai P, Jia R, Fan X. Novel insight into the regulatory roles of diverse RNA modifications: Re-defining the bridge between transcription and translation. Mol Cancer. 2020; 19:78. https://doi.org/10.1186/s12943-020-01194-6 [PubMed]
• 10. Zhou H, Rauch S, Dai Q, Cui X, Zhang Z, Nachtergaele S, Sepich C, He C, Dickinson BC. Evolution of a reverse transcriptase to map N¹-methyladenosine in human messenger RNA. Nat Methods. 2019; 16:1281–8. https://doi.org/10.1038/s41592-019-0550-4 [PubMed]
• 11. Yang Y, Hsu PJ, Chen YS, Yang YG. Dynamic transcriptomic m⁶A decoration: writers, erasers, readers and functions in RNA metabolism. Cell Res. 2018; 28:616–24. https://doi.org/10.1038/s41422-018-0040-8 [PubMed]
• 12. Arango D, Sturgill D, Alhusaini N, Dillman AA, Sweet TJ, Hanson G, Hosogane M, Sinclair WR, Nanan KK, Mandler MD, Fox SD, Zengeya TT, Andresson T, et al. Acetylation of Cytidine in mRNA Promotes Translation Efficiency. Cell. 2018; 175:1872–86.e24. https://doi.org/10.1016/j.cell.2018.10.030 [PubMed]
• 13. Pandolfini L, Barbieri I, Bannister AJ, Hendrick A, Andrews B, Webster N, Murat P, Mach P, Brandi R, Robson SC, Migliori V, Alendar A, d'Onofrio M, et al. METTL1 Promotes let-7 MicroRNA Processing via m7G Methylation. Mol Cell. 2019; 74:1278–90.e9. https://doi.org/10.1016/j.molcel.2019.03.040 [PubMed]
• 14. Haruehanroengra P, Zheng YY, Zhou Y, Huang Y, Sheng J. RNA modifications and cancer. RNA Biol. 2020; 17:1560–75. https://doi.org/10.1080/15476286.2020.1722449 [PubMed]
• 15. Zaccara S, Ries RJ, Jaffrey SR. Reading, writing and erasing mRNA methylation. Nat Rev Mol Cell Biol. 2019; 20:608–24. https://doi.org/10.1038/s41580-019-0168-5 [PubMed]
• 16. Lence T, Paolantoni C, Worpenberg L, Roignant JY. Mechanistic insights into m⁶A RNA enzymes. Biochim Biophys Acta Gene Regul Mech. 2019; 1862:222–9. https://doi.org/10.1016/j.bbagrm.2018.10.014 [PubMed]
• 17. Sun T, Wu R, Ming L. The role of m6A RNA methylation in cancer. Biomed Pharmacother. 2019; 112:108613. https://doi.org/10.1016/j.biopha.2019.108613 [PubMed]
• 18. Su R, Dong L, Li Y, Gao M, He PC, Liu W, Wei J, Zhao Z, Gao L, Han L, Deng X, Li C, Prince E, et al. METTL16 exerts an m⁶A-independent function to facilitate translation and tumorigenesis. Nat Cell Biol. 2022; 24:205–16. https://doi.org/10.1038/s41556-021-00835-2 [PubMed]
• 19. Kan RL, Chen J, Sallam T. Crosstalk between epitranscriptomic and epigenetic mechanisms in gene regulation. Trends Genet. 2022; 38:182–93. https://doi.org/10.1016/j.tig.2021.06.014 [PubMed]
• 20. Wang X, Zhao BS, Roundtree IA, Lu Z, Han D, Ma H, Weng X, Chen K, Shi H, He C. N(6)-methyladenosine Modulates Messenger RNA Translation Efficiency. Cell. 2015; 161:1388–99. https://doi.org/10.1016/j.cell.2015.05.014 [PubMed]
• 21. Ping XL, Sun BF, Wang L, Xiao W, Yang X, Wang WJ, Adhikari S, Shi Y, Lv Y, Chen YS, Zhao X, Li A, Yang Y, et al. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res. 2014; 24:177–89. https://doi.org/10.1038/cr.2014.3 [PubMed]
• 22. Patil DP, Chen CK, Pickering BF, Chow A, Jackson C, Guttman M, Jaffrey SR. m⁶A RNA methylation promotes XIST-mediated transcriptional repression. Nature. 2016; 537:369–73. https://doi.org/10.1038/nature19342 [PubMed]
• 23. Yue Y, Liu J, Cui X, Cao J, Luo G, Zhang Z, Cheng T, Gao M, Shu X, Ma H, Wang F, Wang X, Shen B, et al. VIRMA mediates preferential m(6)A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell Discov. 2018; 4:10. https://doi.org/10.1038/s41421-018-0019-0 [PubMed]
• 24. Zhang C, Chen Y, Sun B, Wang L, Yang Y, Ma D, Lv J, Heng J, Ding Y, Xue Y, Lu X, Xiao W, Yang YG, Liu F. m⁶A modulates haematopoietic stem and progenitor cell specification. Nature. 2017; 549:273–6. https://doi.org/10.1038/nature23883 [PubMed]
• 25. Shafik AM, Zhang F, Guo Z, Dai Q, Pajdzik K, Li Y, Kang Y, Yao B, Wu H, He C, Allen EG, Duan R, Jin P. N6-methyladenosine dynamics in neurodevelopment and aging, and its potential role in Alzheimer's disease. Genome Biol. 2021; 22:17. https://doi.org/10.1186/s13059-020-02249-z [PubMed]
• 26. Ruszkowska A. METTL16, Methyltransferase-Like Protein 16: Current Insights into Structure and Function. Int J Mol Sci. 2021; 22:2176. https://doi.org/10.3390/ijms22042176 [PubMed]
• 27. Mauer J, Luo X, Blanjoie A, Jiao X, Grozhik AV, Patil DP, Linder B, Pickering BF, Vasseur JJ, Chen Q, Gross SS, Elemento O, Debart F, et al. Reversible methylation of m⁶A_m in the 5' cap controls mRNA stability. Nature. 2017; 541:371–5. https://doi.org/10.1038/nature21022 [PubMed]
• 28. Wei J, Liu F, Lu Z, Fei Q, Ai Y, He PC, Shi H, Cui X, Su R, Klungland A, Jia G, Chen J, He C. Differential m⁶A, m⁶A_m, and m¹A Demethylation Mediated by FTO in the Cell Nucleus and Cytoplasm. Mol Cell. 2018; 71:973–85.e5. https://doi.org/10.1016/j.molcel.2018.08.011 [PubMed]
• 29. Zheng G, Dahl JA, Niu Y, Fedorcsak P, Huang CM, Li CJ, Vågbø CB, Shi Y, Wang WL, Song SH, Lu Z, Bosmans RP, Dai Q, et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell. 2013; 49:18–29. https://doi.org/10.1016/j.molcel.2012.10.015 [PubMed]
• 30. Zhu LY, Zhu YR, Dai DJ, Wang X, Jin HC. Epigenetic regulation of alternative splicing. Am J Cancer Res. 2018; 8:2346–58. [PubMed]
• 31. Melstrom L, Chen J. RNA N⁶-methyladenosine modification in solid tumors: new therapeutic frontiers. Cancer Gene Ther. 2020; 27:625–33. https://doi.org/10.1038/s41417-020-0160-4 [PubMed]
• 32. Zhao Y, Shi Y, Shen H, Xie W. m⁶A-binding proteins: the emerging crucial performers in epigenetics. J Hematol Oncol. 2020; 13:35. https://doi.org/10.1186/s13045-020-00872-8 [PubMed]
• 33. Patil DP, Pickering BF, Jaffrey SR. Reading m⁶A in the Transcriptome: m⁶A-Binding Proteins. Trends Cell Biol. 2018; 28:113–27. https://doi.org/10.1016/j.tcb.2017.10.001 [PubMed]
• 34. Roundtree IA, Luo GZ, Zhang Z, Wang X, Zhou T, Cui Y, Sha J, Huang X, Guerrero L, Xie P, He E, Shen B, He C. YTHDC1 mediates nuclear export of N⁶-methyladenosine methylated mRNAs. Elife. 2017; 6:e31311. https://doi.org/10.7554/eLife.31311 [PubMed]
• 35. Xiao W, Adhikari S, Dahal U, Chen YS, Hao YJ, Sun BF, Sun HY, Li A, Ping XL, Lai WY, Wang X, Ma HL, Huang CM, et al. Nuclear m(6)A Reader YTHDC1 Regulates mRNA Splicing. Mol Cell. 2016; 61:507–19. https://doi.org/10.1016/j.molcel.2016.01.012 [PubMed]
• 36. Wang X, Lu Z, Gomez A, Hon GC, Yue Y, Han D, Fu Y, Parisien M, Dai Q, Jia G, Ren B, Pan T, He C. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature. 2014; 505:117–20. https://doi.org/10.1038/nature12730 [PubMed]
• 37. Du H, Zhao Y, He J, Zhang Y, Xi H, Liu M, Ma J, Wu L. YTHDF2 destabilizes m(6)A-containing RNA through direct recruitment of the CCR4-NOT deadenylase complex. Nat Commun. 2016; 7:12626. https://doi.org/10.1038/ncomms12626 [PubMed]
• 38. Wu E, Vashisht AA, Chapat C, Flamand MN, Cohen E, Sarov M, Tabach Y, Sonenberg N, Wohlschlegel J, Duchaine TF. A continuum of mRNP complexes in embryonic microRNA-mediated silencing. Nucleic Acids Res. 2017; 45:2081–98. https://doi.org/10.1093/nar/gkw872 [PubMed]
• 39. Shi H, Wang X, Lu Z, Zhao BS, Ma H, Hsu PJ, Liu C, He C. YTHDF3 facilitates translation and decay of N⁶-methyladenosine-modified RNA. Cell Res. 2017; 27:315–28. https://doi.org/10.1038/cr.2017.15 [PubMed]
• 40. Zaccara S, Jaffrey SR. A Unified Model for the Function of YTHDF Proteins in Regulating m⁶A-Modified mRNA. Cell. 2020; 181:1582–95.e18. https://doi.org/10.1016/j.cell.2020.05.012 [PubMed]
• 41. Zhang L, Hou C, Chen C, Guo Y, Yuan W, Yin D, Liu J, Sun Z. The role of N⁶-methyladenosine (m⁶A) modification in the regulation of circRNAs. Mol Cancer. 2020; 19:105. https://doi.org/10.1186/s12943-020-01224-3 [PubMed]
• 42. Alarcón CR, Goodarzi H, Lee H, Liu X, Tavazoie S, Tavazoie SF. HNRNPA2B1 Is a Mediator of m(6)A-Dependent Nuclear RNA Processing Events. Cell. 2015; 162:1299–308. https://doi.org/10.1016/j.cell.2015.08.011 [PubMed]
• 43. Piñol-Roma S, Dreyfuss G. Cell cycle-regulated phosphorylation of the pre-mRNA-binding (heterogeneous nuclear ribonucleoprotein) C proteins. Mol Cell Biol. 1993; 13:5762–70. https://doi.org/10.1128/mcb.13.9.5762-5770.1993 [PubMed]
• 44. Zhou KI, Shi H, Lyu R, Wylder AC, Matuszek Ż, Pan JN, He C, Parisien M, Pan T. Regulation of Co-transcriptional Pre-mRNA Splicing by m⁶A through the Low-Complexity Protein hnRNPG. Mol Cell. 2019; 76:70–81.e9. https://doi.org/10.1016/j.molcel.2019.07.005 [PubMed]
• 45. Meyer KD, Patil DP, Zhou J, Zinoviev A, Skabkin MA, Elemento O, Pestova TV, Qian SB, Jaffrey SR. 5' UTR m(6)A Promotes Cap-Independent Translation. Cell. 2015; 163:999–1010. https://doi.org/10.1016/j.cell.2015.10.012 [PubMed]
• 46. des Georges A, Dhote V, Kuhn L, Hellen CU, Pestova TV, Frank J, Hashem Y. Structure of mammalian eIF3 in the context of the 43S preinitiation complex. Nature. 2015; 525:491–5. https://doi.org/10.1038/nature14891 [PubMed]
• 47. Huang H, Weng H, Sun W, Qin X, Shi H, Wu H, Zhao BS, Mesquita A, Liu C, Yuan CL, Hu YC, Hüttelmaier S, Skibbe JR, et al. Recognition of RNA N⁶-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat Cell Biol. 2018; 20:285–95. https://doi.org/10.1038/s41556-018-0045-z [PubMed]
• 48. Chen B, Li Y, Song R, Xue C, Xu F. Functions of RNA N6-methyladenosine modification in cancer progression. Mol Biol Rep. 2019; 46:2567–75. https://doi.org/10.1007/s11033-019-04655-4 [PubMed]
• 49. Ma S, Chen C, Ji X, Liu J, Zhou Q, Wang G, Yuan W, Kan Q, Sun Z. The interplay between m6A RNA methylation and noncoding RNA in cancer. J Hematol Oncol. 2019; 12:121. https://doi.org/10.1186/s13045-019-0805-7 [PubMed]
• 50. Pan Y, Ma P, Liu Y, Li W, Shu Y. Multiple functions of m⁶A RNA methylation in cancer. J Hematol Oncol. 2018; 11:48. https://doi.org/10.1186/s13045-018-0590-8 [PubMed]
• 51. Liu S, Li G, Li Q, Zhang Q, Zhuo L, Chen X, Zhai B, Sui X, Chen K, Xie T. The roles and mechanisms of YTH domain-containing proteins in cancer development and progression. Am J Cancer Res. 2020; 10:1068–84. [PubMed]
• 52. Visvanathan A, Patil V, Arora A, Hegde AS, Arivazhagan A, Santosh V, Somasundaram K. Essential role of METTL3-mediated m⁶A modification in glioma stem-like cells maintenance and radioresistance. Oncogene. 2018; 37:522–33. https://doi.org/10.1038/onc.2017.351 [PubMed]
• 53. Wang Q, Chen C, Ding Q, Zhao Y, Wang Z, Chen J, Jiang Z, Zhang Y, Xu G, Zhang J, Zhou J, Sun B, Zou X, Wang S. METTL3-mediated m⁶A modification of HDGF mRNA promotes gastric cancer progression and has prognostic significance. Gut. 2020; 69:1193–205. https://doi.org/10.1136/gutjnl-2019-319639 [PubMed]
• 54. Chen M, Wei L, Law CT, Tsang FH, Shen J, Cheng CL, Tsang LH, Ho DW, Chiu DK, Lee JM, Wong CC, Ng IO, Wong CM. RNA N6-methyladenosine methyltransferase-like 3 promotes liver cancer progression through YTHDF2-dependent posttranscriptional silencing of SOCS2. Hepatology. 2018; 67:2254–70. https://doi.org/10.1002/hep.29683 [PubMed]
• 55. Liu L, Wang J, Sun G, Wu Q, Ma J, Zhang X, Huang N, Bian Z, Gu S, Xu M, Yin M, Sun F, Pan Q. m⁶A mRNA methylation regulates CTNNB1 to promote the proliferation of hepatoblastoma. Mol Cancer. 2019; 18:188. https://doi.org/10.1186/s12943-019-1119-7 [PubMed]
• 56. Zhu W, Si Y, Xu J, Lin Y, Wang JZ, Cao M, Sun S, Ding Q, Zhu L, Wei JF. Methyltransferase like 3 promotes colorectal cancer proliferation by stabilizing CCNE1 mRNA in an m6A-dependent manner. J Cell Mol Med. 2020; 24:3521–33. https://doi.org/10.1111/jcmm.15042 [PubMed]
• 57. Gao Q, Zheng J, Ni Z, Sun P, Yang C, Cheng M, Wu M, Zhang X, Yuan L, Zhang Y, Li Y. The m⁶A Methylation-Regulated AFF4 Promotes Self-Renewal of Bladder Cancer Stem Cells. Stem Cells Int. 2020; 2020:8849218. https://doi.org/10.1155/2020/8849218 [PubMed]
• 58. Cheng M, Sheng L, Gao Q, Xiong Q, Zhang H, Wu M, Liang Y, Zhu F, Zhang Y, Zhang X, Yuan Q, Li Y. The m⁶A methyltransferase METTL3 promotes bladder cancer progression via AFF4/NF-κB/MYC signaling network. Oncogene. 2019; 38:3667–80. https://doi.org/10.1038/s41388-019-0683-z [PubMed]
• 59. Wanna-Udom S, Terashima M, Lyu H, Ishimura A, Takino T, Sakari M, Tsukahara T, Suzuki T. The m6A methyltransferase METTL3 contributes to Transforming Growth Factor-beta-induced epithelial-mesenchymal transition of lung cancer cells through the regulation of JUNB. Biochem Biophys Res Commun. 2020; 524:150–5. https://doi.org/10.1016/j.bbrc.2020.01.042 [PubMed]
• 60. Choe J, Lin S, Zhang W, Liu Q, Wang L, Ramirez-Moya J, Du P, Kim W, Tang S, Sliz P, Santisteban P, George RE, Richards WG, et al. mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis. Nature. 2018; 561:556–60. https://doi.org/10.1038/s41586-018-0538-8 [PubMed]
• 61. Zhou R, Gao Y, Lv D, Wang C, Wang D, Li Q. METTL3 mediated m⁶A modification plays an oncogenic role in cutaneous squamous cell carcinoma by regulating ΔNp63. Biochem Biophys Res Commun. 2019; 515:310–7. https://doi.org/10.1016/j.bbrc.2019.05.155 [PubMed]
• 62. Taketo K, Konno M, Asai A, Koseki J, Toratani M, Satoh T, Doki Y, Mori M, Ishii H, Ogawa K. The epitranscriptome m6A writer METTL3 promotes chemo- and radioresistance in pancreatic cancer cells. Int J Oncol. 2018; 52:621–9. https://doi.org/10.3892/ijo.2017.4219 [PubMed]
• 63. Cui Q, Shi H, Ye P, Li L, Qu Q, Sun G, Sun G, Lu Z, Huang Y, Yang CG, Riggs AD, He C, Shi Y. m⁶A RNA Methylation Regulates the Self-Renewal and Tumorigenesis of Glioblastoma Stem Cells. Cell Rep. 2017; 18:2622–34. https://doi.org/10.1016/j.celrep.2017.02.059 [PubMed]
• 64. Zhang J, Bai R, Li M, Ye H, Wu C, Wang C, Li S, Tan L, Mai D, Li G, Pan L, Zheng Y, Su J, et al. Excessive miR-25-3p maturation via N⁶-methyladenosine stimulated by cigarette smoke promotes pancreatic cancer progression. Nat Commun. 2019; 10:1858. https://doi.org/10.1038/s41467-019-09712-x [PubMed]
• 65. Yang F, Yuan WQ, Li J, Luo YQ. Knockdown of METTL14 suppresses the malignant progression of non-small cell lung cancer by reducing Twist expression. Oncol Lett. 2021; 22:847. https://doi.org/10.3892/ol.2021.13108 [PubMed]
• 66. Weng H, Huang H, Wu H, Qin X, Zhao BS, Dong L, Shi H, Skibbe J, Shen C, Hu C, Sheng Y, Wang Y, Wunderlich M, et al. METTL14 Inhibits Hematopoietic Stem/Progenitor Differentiation and Promotes Leukemogenesis via mRNA m⁶A Modification. Cell Stem Cell. 2018; 22:191–205.e9. https://doi.org/10.1016/j.stem.2017.11.016 [PubMed]
• 67. Chen Y, Peng C, Chen J, Chen D, Yang B, He B, Hu W, Zhang Y, Liu H, Dai L, Xie H, Zhou L, Wu J, Zheng S. WTAP facilitates progression of hepatocellular carcinoma via m6A-HuR-dependent epigenetic silencing of ETS1. Mol Cancer. 2019; 18:127. https://doi.org/10.1186/s12943-019-1053-8 [PubMed]
• 68. Naren D, Yan T, Gong Y, Huang J, Zhang D, Sang L, Zheng X, Li Y. High Wilms' tumor 1 associating protein expression predicts poor prognosis in acute myeloid leukemia and regulates m⁶A methylation of MYC mRNA. J Cancer Res Clin Oncol. 2021; 147:33–47. https://doi.org/10.1007/s00432-020-03373-w [PubMed]
• 69. Qian JY, Gao J, Sun X, Cao MD, Shi L, Xia TS, Zhou WB, Wang S, Ding Q, Wei JF. KIAA1429 acts as an oncogenic factor in breast cancer by regulating CDK1 in an N6-methyladenosine-independent manner. Oncogene. 2019; 38:6123–41. https://doi.org/10.1038/s41388-019-0861-z [PubMed]
• 70. Lan T, Li H, Zhang D, Xu L, Liu H, Hao X, Yan X, Liao H, Chen X, Xie K, Li J, Liao M, Huang J, et al. KIAA1429 contributes to liver cancer progression through N6-methyladenosine-dependent post-transcriptional modification of GATA3. Mol Cancer. 2019; 18:186. https://doi.org/10.1186/s12943-019-1106-z [PubMed]
• 71. Li Z, Weng H, Su R, Weng X, Zuo Z, Li C, Huang H, Nachtergaele S, Dong L, Hu C, Qin X, Tang L, Wang Y, et al. FTO Plays an Oncogenic Role in Acute Myeloid Leukemia as a N⁶-Methyladenosine RNA Demethylase. Cancer Cell. 2017; 31:127–41. https://doi.org/10.1016/j.ccell.2016.11.017 [PubMed]
• 72. Qing Y, Dong L, Gao L, Li C, Li Y, Han L, Prince E, Tan B, Deng X, Wetzel C, Shen C, Gao M, Chen Z, et al. R-2-hydroxyglutarate attenuates aerobic glycolysis in leukemia by targeting the FTO/m⁶A/PFKP/LDHB axis. Mol Cell. 2021; 81:922–39.e9. https://doi.org/10.1016/j.molcel.2020.12.026 [PubMed]
• 73. Niu Y, Lin Z, Wan A, Chen H, Liang H, Sun L, Wang Y, Li X, Xiong XF, Wei B, Wu X, Wan G. RNA N6-methyladenosine demethylase FTO promotes breast tumor progression through inhibiting BNIP3. Mol Cancer. 2019; 18:46. https://doi.org/10.1186/s12943-019-1004-4 [PubMed]
• 74. Yang S, Wei J, Cui YH, Park G, Shah P, Deng Y, Aplin AE, Lu Z, Hwang S, He C, He YY. m⁶A mRNA demethylase FTO regulates melanoma tumorigenicity and response to anti-PD-1 blockade. Nat Commun. 2019; 10:2782. https://doi.org/10.1038/s41467-019-10669-0 [PubMed]
• 75. Liu Y, Liang G, Xu H, Dong W, Dong Z, Qiu Z, Zhang Z, Li F, Huang Y, Li Y, Wu J, Yin S, Zhang Y, et al. Tumors exploit FTO-mediated regulation of glycolytic metabolism to evade immune surveillance. Cell Metab. 2021; 33:1221–33.e11. https://doi.org/10.1016/j.cmet.2021.04.001 [PubMed]
• 76. Xiao L, Li X, Mu Z, Zhou J, Zhou P, Xie C, Jiang S. FTO Inhibition Enhances the Antitumor Effect of Temozolomide by Targeting MYC-miR-155/23a Cluster-MXI1 Feedback Circuit in Glioma. Cancer Res. 2020; 80:3945–58. https://doi.org/10.1158/0008-5472.CAN-20-0132 [PubMed]
• 77. Huang Y, Su R, Sheng Y, Dong L, Dong Z, Xu H, Ni T, Zhang ZS, Zhang T, Li C, Han L, Zhu Z, Lian F, et al. Small-Molecule Targeting of Oncogenic FTO Demethylase in Acute Myeloid Leukemia. Cancer Cell. 2019; 35:677–91.e10. https://doi.org/10.1016/j.ccell.2019.03.006 [PubMed]
• 78. Yang X, Shao F, Guo D, Wang W, Wang J, Zhu R, Gao Y, He J, Lu Z. WNT/β-catenin-suppressed FTO expression increases m⁶A of c-Myc mRNA to promote tumor cell glycolysis and tumorigenesis. Cell Death Dis. 2021; 12:462. https://doi.org/10.1038/s41419-021-03739-z [PubMed]
• 79. Rong ZX, Li Z, He JJ, Liu LY, Ren XX, Gao J, Mu Y, Guan YD, Duan YM, Zhang XP, Zhang DX, Li N, Deng YZ, Sun LQ. Downregulation of Fat Mass and Obesity Associated (FTO) Promotes the Progression of Intrahepatic Cholangiocarcinoma. Front Oncol. 2019; 9:369. https://doi.org/10.3389/fonc.2019.00369 [PubMed]
• 80. Zhang S, Zhao BS, Zhou A, Lin K, Zheng S, Lu Z, Chen Y, Sulman EP, Xie K, Bögler O, Majumder S, He C, Huang S. m⁶A Demethylase ALKBH5 Maintains Tumorigenicity of Glioblastoma Stem-like Cells by Sustaining FOXM1 Expression and Cell Proliferation Program. Cancer Cell. 2017; 31:591–606.e6. https://doi.org/10.1016/j.ccell.2017.02.013 [PubMed]
• 81. Shen C, Sheng Y, Zhu AC, Robinson S, Jiang X, Dong L, Chen H, Su R, Yin Z, Li W, Deng X, Chen Y, Hu YC, et al. RNA Demethylase ALKBH5 Selectively Promotes Tumorigenesis and Cancer Stem Cell Self-Renewal in Acute Myeloid Leukemia. Cell Stem Cell. 2020; 27:64–80.e9. https://doi.org/10.1016/j.stem.2020.04.009 [PubMed]
• 82. Zhu H, Gan X, Jiang X, Diao S, Wu H, Hu J. ALKBH5 inhibited autophagy of epithelial ovarian cancer through miR-7 and BCL-2. J Exp Clin Cancer Res. 2019; 38:163. https://doi.org/10.1186/s13046-019-1159-2 [PubMed]
• 83. Chen Y, Zhao Y, Chen J, Peng C, Zhang Y, Tong R, Cheng Q, Yang B, Feng X, Lu Y, Xie H, Zhou L, Wu J, Zheng S. ALKBH5 suppresses malignancy of hepatocellular carcinoma via m⁶A-guided epigenetic inhibition of LYPD1. Mol Cancer. 2020; 19:123. https://doi.org/10.1186/s12943-020-01239-w [PubMed]
• 84. Liu X, Qin J, Gao T, Li C, He B, Pan B, Xu X, Chen X, Zeng K, Xu M, Zhu C, Pan Y, Sun H, et al. YTHDF1 Facilitates the Progression of Hepatocellular Carcinoma by Promoting FZD5 mRNA Translation in an m6A-Dependent Manner. Mol Ther Nucleic Acids. 2020; 22:750–65. https://doi.org/10.1016/j.omtn.2020.09.036 [PubMed]. Retraction in: Mol Ther Nucleic Acids. 2022; 28:571. https://doi.org/10.1016/j.omtn.2022.04.027 [PubMed]
• 85. Anita R, Paramasivam A, Priyadharsini JV, Chitra S. The m6A readers YTHDF1 and YTHDF3 aberrations associated with metastasis and predict poor prognosis in breast cancer patients. Am J Cancer Res. 2020; 10:2546–54. [PubMed]
• 86. Shi Y, Fan S, Wu M, Zuo Z, Li X, Jiang L, Shen Q, Xu P, Zeng L, Zhou Y, Huang Y, Yang Z, Zhou J, et al. YTHDF1 links hypoxia adaptation and non-small cell lung cancer progression. Nat Commun. 2019; 10:4892. https://doi.org/10.1038/s41467-019-12801-6 [PubMed]
• 87. Bai Y, Yang C, Wu R, Huang L, Song S, Li W, Yan P, Lin C, Li D, Zhang Y. YTHDF1 Regulates Tumorigenicity and Cancer Stem Cell-Like Activity in Human Colorectal Carcinoma. Front Oncol. 2019; 9:332. https://doi.org/10.3389/fonc.2019.00332 [PubMed]
• 88. Orouji E, Peitsch WK, Orouji A, Houben R, Utikal J. Oncogenic Role of an Epigenetic Reader of m⁶A RNA Modification: YTHDF1 in Merkel Cell Carcinoma. Cancers (Basel). 2020; 12:202. https://doi.org/10.3390/cancers12010202 [PubMed]
• 89. Nishizawa Y, Konno M, Asai A, Koseki J, Kawamoto K, Miyoshi N, Takahashi H, Nishida N, Haraguchi N, Sakai D, Kudo T, Hata T, Matsuda C, et al. Oncogene c-Myc promotes epitranscriptome m⁶A reader YTHDF1 expression in colorectal cancer. Oncotarget. 2017; 9:7476–86. https://doi.org/10.18632/oncotarget.23554 [PubMed]
• 90. Han D, Liu J, Chen C, Dong L, Liu Y, Chang R, Huang X, Liu Y, Wang J, Dougherty U, Bissonnette MB, Shen B, Weichselbaum RR, et al. Anti-tumour immunity controlled through mRNA m⁶A methylation and YTHDF1 in dendritic cells. Nature. 2019; 566:270–4. https://doi.org/10.1038/s41586-019-0916-x [PubMed]
• 91. Jia R, Chai P, Wang S, Sun B, Xu Y, Yang Y, Ge S, Jia R, Yang YG, Fan X. m⁶A modification suppresses ocular melanoma through modulating HINT2 mRNA translation. Mol Cancer. 2019; 18:161. https://doi.org/10.1186/s12943-019-1088-x [PubMed]
• 92. Paris J, Morgan M, Campos J, Spencer GJ, Shmakova A, Ivanova I, Mapperley C, Lawson H, Wotherspoon DA, Sepulveda C, Vukovic M, Allen L, Sarapuu A, et al. Targeting the RNA m⁶A Reader YTHDF2 Selectively Compromises Cancer Stem Cells in Acute Myeloid Leukemia. Cell Stem Cell. 2019; 25:137–48.e6. https://doi.org/10.1016/j.stem.2019.03.021 [PubMed]
• 93. Chen J, Sun Y, Xu X, Wang D, He J, Zhou H, Lu Y, Zeng J, Du F, Gong A, Xu M. YTH domain family 2 orchestrates epithelial-mesenchymal transition/proliferation dichotomy in pancreatic cancer cells. Cell Cycle. 2017; 16:2259–71. https://doi.org/10.1080/15384101.2017.1380125 [PubMed]
• 94. Zhong L, Liao D, Zhang M, Zeng C, Li X, Zhang R, Ma H, Kang T. YTHDF2 suppresses cell proliferation and growth via destabilizing the EGFR mRNA in hepatocellular carcinoma. Cancer Lett. 2019; 442:252–61. https://doi.org/10.1016/j.canlet.2018.11.006 [PubMed]
• 95. Hou J, Zhang H, Liu J, Zhao Z, Wang J, Lu Z, Hu B, Zhou J, Zhao Z, Feng M, Zhang H, Shen B, Huang X, et al. YTHDF2 reduction fuels inflammation and vascular abnormalization in hepatocellular carcinoma. Mol Cancer. 2019; 18:163. https://doi.org/10.1186/s12943-019-1082-3 [PubMed]
• 96. Zhang Y, Wang X, Zhang X, Wang J, Ma Y, Zhang L, Cao X. RNA-binding protein YTHDF3 suppresses interferon-dependent antiviral responses by promoting FOXO3 translation. Proc Natl Acad Sci U S A. 2019; 116:976–81. https://doi.org/10.1073/pnas.1812536116 [PubMed]
• 97. Ni W, Yao S, Zhou Y, Liu Y, Huang P, Zhou A, Liu J, Che L, Li J. Long noncoding RNA GAS5 inhibits progression of colorectal cancer by interacting with and triggering YAP phosphorylation and degradation and is negatively regulated by the m⁶A reader YTHDF3. Mol Cancer. 2019; 18:143. https://doi.org/10.1186/s12943-019-1079-y [PubMed]
• 98. Liu X, Liu L, Dong Z, Li J, Yu Y, Chen X, Ren F, Cui G, Sun R. Expression patterns and prognostic value of m⁶A-related genes in colorectal cancer. Am J Transl Res. 2019; 11:3972–91. [PubMed]
• 99. Tanabe A, Tanikawa K, Tsunetomi M, Takai K, Ikeda H, Konno J, Torigoe T, Maeda H, Kutomi G, Okita K, Mori M, Sahara H. RNA helicase YTHDC2 promotes cancer metastasis via the enhancement of the efficiency by which HIF-1α mRNA is translated. Cancer Lett. 2016; 376:34–42. https://doi.org/10.1016/j.canlet.2016.02.022 [PubMed]
• 100. Bell JL, Wächter K, Mühleck B, Pazaitis N, Köhn M, Lederer M, Hüttelmaier S. Insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs): post-transcriptional drivers of cancer progression? Cell Mol Life Sci. 2013; 70:2657–75. https://doi.org/10.1007/s00018-012-1186-z [PubMed]
• 101. Zhang L, Wan Y, Zhang Z, Jiang Y, Gu Z, Ma X, Nie S, Yang J, Lang J, Cheng W, Zhu L. IGF2BP1 overexpression stabilizes PEG10 mRNA in an m6A-dependent manner and promotes endometrial cancer progression. Theranostics. 2021; 11:1100–14. https://doi.org/10.7150/thno.49345 [PubMed]
• 102. He RZ, Jiang J, Luo DX. M6A modification of circNSUN2 promotes colorectal liver metastasis. Genes Dis. 2019; 8:6–7. https://doi.org/10.1016/j.gendis.2019.12.002 [PubMed]
• 103. Huang H, Weng H, Chen J. m⁶A Modification in Coding and Non-coding RNAs: Roles and Therapeutic Implications in Cancer. Cancer Cell. 2020; 37:270–88. https://doi.org/10.1016/j.ccell.2020.02.004 [PubMed]
• 104. Li H, Wu H, Wang Q, Ning S, Xu S, Pang D. Dual effects of N⁶-methyladenosine on cancer progression and immunotherapy. Mol Ther Nucleic Acids. 2021; 24:25–39. https://doi.org/10.1016/j.omtn.2021.02.001 [PubMed]
• 105. Erson-Bensan AE, Begik O. m6A Modification and Implications for microRNAs. Microrna. 2017; 6:97–101. https://doi.org/10.2174/2211536606666170511102219 [PubMed]
• 106. Meyer KD, Jaffrey SR. The dynamic epitranscriptome: N6-methyladenosine and gene expression control. Nat Rev Mol Cell Biol. 2014; 15:313–26. https://doi.org/10.1038/nrm3785 [PubMed]
• 107. Alarcón CR, Lee H, Goodarzi H, Halberg N, Tavazoie SF. N6-methyladenosine marks primary microRNAs for processing. Nature. 2015; 519:482–5. https://doi.org/10.1038/nature14281 [PubMed]
• 108. Han J, Wang JZ, Yang X, Yu H, Zhou R, Lu HC, Yuan WB, Lu JC, Zhou ZJ, Lu Q, Wei JF, Yang H. METTL3 promote tumor proliferation of bladder cancer by accelerating pri-miR221/222 maturation in m6A-dependent manner. Mol Cancer. 2019; 18:110. https://doi.org/10.1186/s12943-019-1036-9 [PubMed]
• 109. Peng W, Li J, Chen R, Gu Q, Yang P, Qian W, Ji D, Wang Q, Zhang Z, Tang J, Sun Y. Upregulated METTL3 promotes metastasis of colorectal Cancer via miR-1246/SPRED2/MAPK signaling pathway. J Exp Clin Cancer Res. 2019; 38:393. https://doi.org/10.1186/s13046-019-1408-4 [PubMed]
• 110. Wang H, Deng Q, Lv Z, Ling Y, Hou X, Chen Z, Dinglin X, Ma S, Li D, Wu Y, Peng Y, Huang H, Chen L. N6-methyladenosine induced miR-143-3p promotes the brain metastasis of lung cancer via regulation of VASH1. Mol Cancer. 2019; 18:181. https://doi.org/10.1186/s12943-019-1108-x [PubMed]
• 111. Ma JZ, Yang F, Zhou CC, Liu F, Yuan JH, Wang F, Wang TT, Xu QG, Zhou WP, Sun SH. METTL14 suppresses the metastatic potential of hepatocellular carcinoma by modulating N⁶ -methyladenosine-dependent primary MicroRNA processing. Hepatology. 2017; 65:529–43. https://doi.org/10.1002/hep.28885 [PubMed]
• 112. Chen X, Xu M, Xu X, Zeng K, Liu X, Sun L, Pan B, He B, Pan Y, Sun H, Xia X, Wang S. RETRACTED: METTL14 Suppresses CRC Progression via Regulating N6-Methyladenosine-Dependent Primary miR-375 Processing. Mol Ther. 2020; 28:599–612. https://doi.org/10.1016/j.ymthe.2019.11.016 [PubMed]. Retraction in: Mol Ther. 2022; 30:2640. https://doi.org/10.1016/j.ymthe.2022.03.017 [PubMed]
• 113. Park YM, Hwang SJ, Masuda K, Choi KM, Jeong MR, Nam DH, Gorospe M, Kim HH. Heterogeneous nuclear ribonucleoprotein C1/C2 controls the metastatic potential of glioblastoma by regulating PDCD4. Mol Cell Biol. 2012; 32:4237–44. https://doi.org/10.1128/MCB.00443-12 [PubMed]
• 114. Shah A, Rashid F, Awan HM, Hu S, Wang X, Chen L, Shan G. The DEAD-Box RNA Helicase DDX3 Interacts with m⁶A RNA Demethylase ALKBH5. Stem Cells Int. 2017; 2017:8596135. https://doi.org/10.1155/2017/8596135 [PubMed]
• 115. Han X, Guo J, Fan Z. Interactions between m6A modification and miRNAs in malignant tumors. Cell Death Dis. 2021; 12:598. https://doi.org/10.1038/s41419-021-03868-5 [PubMed]
• 116. Ye S, Song W, Xu X, Zhao X, Yang L. IGF2BP2 promotes colorectal cancer cell proliferation and survival through interfering with RAF-1 degradation by miR-195. FEBS Lett. 2016; 590:1641–50. https://doi.org/10.1002/1873-3468.12205 [PubMed]
• 117. Zhou Y, Huang T, Siu HL, Wong CC, Dong Y, Wu F, Zhang B, Wu WK, Cheng AS, Yu J, To KF, Kang W. IGF2BP3 functions as a potential oncogene and is a crucial target of miR-34a in gastric carcinogenesis. Mol Cancer. 2017; 16:77. https://doi.org/10.1186/s12943-017-0647-2 [PubMed]
• 118. Yang Z, Li J, Feng G, Gao S, Wang Y, Zhang S, Liu Y, Ye L, Li Y, Zhang X. MicroRNA-145 Modulates N⁶-Methyladenosine Levels by Targeting the 3'-Untranslated mRNA Region of the N⁶-Methyladenosine Binding YTH Domain Family 2 Protein. J Biol Chem. 2017; 292:3614–23. https://doi.org/10.1074/jbc.M116.749689 [PubMed]
• 119. Dai F, Wu Y, Lu Y, An C, Zheng X, Dai L, Guo Y, Zhang L, Li H, Xu W, Gao W. Crosstalk between RNA m⁶A Modification and Non-coding RNA Contributes to Cancer Growth and Progression. Mol Ther Nucleic Acids. 2020; 22:62–71. https://doi.org/10.1016/j.omtn.2020.08.004 [PubMed]
• 120. He L, Li H, Wu A, Peng Y, Shu G, Yin G. Functions of N6-methyladenosine and its role in cancer. Mol Cancer. 2019; 18:176. https://doi.org/10.1186/s12943-019-1109-9 [PubMed]
• 121. He RZ, Jiang J, Luo DX. The functions of N6-methyladenosine modification in lncRNAs. Genes Dis. 2020; 7:598–605. https://doi.org/10.1016/j.gendis.2020.03.005 [PubMed]
• 122. Dinescu S, Ignat S, Lazar AD, Constantin C, Neagu M, Costache M. Epitranscriptomic Signatures in lncRNAs and Their Possible Roles in Cancer. Genes (Basel). 2019; 10:52. https://doi.org/10.3390/genes10010052 [PubMed]
• 123. Yang X, Zhang S, He C, Xue P, Zhang L, He Z, Zang L, Feng B, Sun J, Zheng M. METTL14 suppresses proliferation and metastasis of colorectal cancer by down-regulating oncogenic long non-coding RNA XIST. Mol Cancer. 2020; 19:46. https://doi.org/10.1186/s12943-020-1146-4 [PubMed]
• 124. Zhao C, Ling X, Xia Y, Yan B, Guan Q. The m6A methyltransferase METTL3 controls epithelial-mesenchymal transition, migration and invasion of breast cancer through the MALAT1/miR-26b/HMGA2 axis. Cancer Cell Int. 2021; 21:441. https://doi.org/10.1186/s12935-021-02113-5 [PubMed]
• 125. Zuo X, Chen Z, Gao W, Zhang Y, Wang J, Wang J, Cao M, Cai J, Wu J, Wang X. M6A-mediated upregulation of LINC00958 increases lipogenesis and acts as a nanotherapeutic target in hepatocellular carcinoma. J Hematol Oncol. 2020; 13:5. https://doi.org/10.1186/s13045-019-0839-x [PubMed]
• 126. Zheng ZQ, Li ZX, Zhou GQ, Lin L, Zhang LL, Lv JW, Huang XD, Liu RQ, Chen F, He XJ, Kou J, Zhang J, Wen X, et al. Long Noncoding RNA FAM225A Promotes Nasopharyngeal Carcinoma Tumorigenesis and Metastasis by Acting as ceRNA to Sponge miR-590-3p/miR-1275 and Upregulate ITGB3. Cancer Res. 2019; 79:4612–26. https://doi.org/10.1158/0008-5472.CAN-19-0799 [PubMed]
• 127. Wu Y, Yang X, Chen Z, Tian L, Jiang G, Chen F, Li J, An P, Lu L, Luo N, Du J, Shan H, Liu H, Wang H. m⁶A-induced lncRNA RP11 triggers the dissemination of colorectal cancer cells via upregulation of Zeb1. Mol Cancer. 2019; 18:87. https://doi.org/10.1186/s12943-019-1014-2 [PubMed]
• 128. Xue L, Li J, Lin Y, Liu D, Yang Q, Jian J, Peng J. m⁶ A transferase METTL3-induced lncRNA ABHD11-AS1 promotes the Warburg effect of non-small-cell lung cancer. J Cell Physiol. 2021; 236:2649–58. https://doi.org/10.1002/jcp.30023 [PubMed]
• 129. Zhang J, Guo S, Piao HY, Wang Y, Wu Y, Meng XY, Yang D, Zheng ZC, Zhao Y. ALKBH5 promotes invasion and metastasis of gastric cancer by decreasing methylation of the lncRNA NEAT1. J Physiol Biochem. 2019; 75:379–89. https://doi.org/10.1007/s13105-019-00690-8 [PubMed]
• 130. Chen S, Zhou L, Wang Y. ALKBH5-mediated m⁶A demethylation of lncRNA PVT1 plays an oncogenic role in osteosarcoma. Cancer Cell Int. 2020; 20:34. https://doi.org/10.1186/s12935-020-1105-6 [PubMed]
• 131. He Y, Yue H, Cheng Y, Ding Z, Xu Z, Lv C, Wang Z, Wang J, Yin C, Hao H, Chen C. ALKBH5-mediated m⁶A demethylation of KCNK15-AS1 inhibits pancreatic cancer progression via regulating KCNK15 and PTEN/AKT signaling. Cell Death Dis. 2021; 12:1121. https://doi.org/10.1038/s41419-021-04401-4 [PubMed]
• 132. Cui Y, Zhang C, Ma S, Li Z, Wang W, Li Y, Ma Y, Fang J, Wang Y, Cao W, Guan F. RNA m6A demethylase FTO-mediated epigenetic up-regulation of LINC00022 promotes tumorigenesis in esophageal squamous cell carcinoma. J Exp Clin Cancer Res. 2021; 40:294. https://doi.org/10.1186/s13046-021-02096-1 [PubMed]
• 133. Hu X, Peng WX, Zhou H, Jiang J, Zhou X, Huang D, Mo YY, Yang L. IGF2BP2 regulates DANCR by serving as an N6-methyladenosine reader. Cell Death Differ. 2020; 27:1782–94. https://doi.org/10.1038/s41418-019-0461-z [PubMed]
• 134. Ye M, Dong S, Hou H, Zhang T, Shen M. Oncogenic Role of Long Noncoding RNAMALAT1 in Thyroid Cancer Progression through Regulation of the miR-204/IGF2BP2/m6A-MYC Signaling. Mol Ther Nucleic Acids. 2020; 23:1–12. https://doi.org/10.1016/j.omtn.2020.09.023 [PubMed]
• 135. Wang Y, Lu JH, Wu QN, Jin Y, Wang DS, Chen YX, Liu J, Luo XJ, Meng Q, Pu HY, Wang YN, Hu PS, Liu ZX, et al. LncRNA LINRIS stabilizes IGF2BP2 and promotes the aerobic glycolysis in colorectal cancer. Mol Cancer. 2019; 18:174. https://doi.org/10.1186/s12943-019-1105-0 [PubMed]
• 136. Yan J, Huang X, Zhang X, Chen Z, Ye C, Xiang W, Huang Z. LncRNA LINC00470 promotes the degradation of PTEN mRNA to facilitate malignant behavior in gastric cancer cells. Biochem Biophys Res Commun. 2020; 521:887–93. https://doi.org/10.1016/j.bbrc.2019.11.016 [PubMed]
• 137. Zhu P, He F, Hou Y, Tu G, Li Q, Jin T, Zeng H, Qin Y, Wan X, Qiao Y, Qiu Y, Teng Y, Liu M. A novel hypoxic long noncoding RNA KB-1980E6.3 maintains breast cancer stem cell stemness via interacting with IGF2BP1 to facilitate c-Myc mRNA stability. Oncogene. 2021; 40:1609–27. https://doi.org/10.1038/s41388-020-01638-9 [PubMed]
• 138. Zhu L, Zhu Y, Han S, Chen M, Song P, Dai D, Xu W, Jiang T, Feng L, Shin VY, Wang X, Jin H. Impaired autophagic degradation of lncRNA ARHGAP5-AS1 promotes chemoresistance in gastric cancer. Cell Death Dis. 2019; 10:383. https://doi.org/10.1038/s41419-019-1585-2 [PubMed]
• 139. Chen LL, Yang L. Regulation of circRNA biogenesis. RNA Biol. 2015; 12:381–8. https://doi.org/10.1080/15476286.2015.1020271 [PubMed]
• 140. Wang X, Ma R, Zhang X, Cui L, Ding Y, Shi W, Guo C, Shi Y. Crosstalk between N6-methyladenosine modification and circular RNAs: current understanding and future directions. Mol Cancer. 2021; 20:121. https://doi.org/10.1186/s12943-021-01415-6 [PubMed]
• 141. Meng Y, Hao D, Huang Y, Jia S, Zhang J, He X, Liu D, Sun L. Circular RNA circNRIP1 plays oncogenic roles in the progression of osteosarcoma. Mamm Genome. 2021; 32:448–56. https://doi.org/10.1007/s00335-021-09891-3 [PubMed]
• 142. Guo Y, Guo Y, Chen C, Fan D, Wu X, Zhao L, Shao B, Sun Z, Ji Z. Circ3823 contributes to growth, metastasis and angiogenesis of colorectal cancer: involvement of miR-30c-5p/TCF7 axis. Mol Cancer. 2021; 20:93. https://doi.org/10.1186/s12943-021-01372-0 [PubMed]
• 143. Li Z, Yang HY, Dai XY, Zhang X, Huang YZ, Shi L, Wei JF, Ding Q. CircMETTL3, upregulated in a m6A-dependent manner, promotes breast cancer progression. Int J Biol Sci. 2021; 17:1178–90. https://doi.org/10.7150/ijbs.57783 [PubMed]
• 144. Ji F, Lu Y, Chen S, Yu Y, Lin X, Zhu Y, Luo X. IGF2BP2-modified circular RNA circARHGAP12 promotes cervical cancer progression by interacting m⁶A/FOXM1 manner. Cell Death Discov. 2021; 7:215. https://doi.org/10.1038/s41420-021-00595-w [PubMed]
• 145. Zhao J, Lee EE, Kim J, Yang R, Chamseddin B, Ni C, Gusho E, Xie Y, Chiang CM, Buszczak M, Zhan X, Laimins L, Wang RC. Transforming activity of an oncoprotein-encoding circular RNA from human papillomavirus. Nat Commun. 2019; 10:2300. https://doi.org/10.1038/s41467-019-10246-5 [PubMed]
• 146. Chen C, Yuan W, Zhou Q, Shao B, Guo Y, Wang W, Yang S, Guo Y, Zhao L, Dang Q, Yang X, Wang G, Kang Q, et al. N6-methyladenosine-induced circ1662 promotes metastasis of colorectal cancer by accelerating YAP1 nuclear localization. Theranostics. 2021; 11:4298–315. https://doi.org/10.7150/thno.51342 [PubMed]
• 147. Chen RX, Chen X, Xia LP, Zhang JX, Pan ZZ, Ma XD, Han K, Chen JW, Judde JG, Deas O, Wang F, Ma NF, Guan X, et al. N⁶-methyladenosine modification of circNSUN2 facilitates cytoplasmic export and stabilizes HMGA2 to promote colorectal liver metastasis. Nat Commun. 2019; 10:4695. https://doi.org/10.1038/s41467-019-12651-2 [PubMed]
• 148. Rong D, Wu F, Lu C, Sun G, Shi X, Chen X, Dai Y, Zhong W, Hao X, Zhou J, Xia Y, Tang W, Wang X. m6A modification of circHPS5 and hepatocellular carcinoma progression through HMGA2 expression. Mol Ther Nucleic Acids. 2021; 26:637–48. https://doi.org/10.1016/j.omtn.2021.09.001 [PubMed]
• 149. Rao X, Lai L, Li X, Wang L, Li A, Yang Q. N⁶ -methyladenosine modification of circular RNA circ-ARL3 facilitates Hepatitis B virus-associated hepatocellular carcinoma via sponging miR-1305. IUBMB Life. 2021; 73:408–17. https://doi.org/10.1002/iub.2438 [PubMed]
• 150. Liu Z, Wang T, She Y, Wu K, Gu S, Li L, Dong C, Chen C, Zhou Y. N⁶-methyladenosine-modified circIGF2BP3 inhibits CD8⁺ T-cell responses to facilitate tumor immune evasion by promoting the deubiquitination of PD-L1 in non-small cell lung cancer. Mol Cancer. 2021; 20:105. https://doi.org/10.1186/s12943-021-01398-4 [PubMed]
• 151. Sun HD, Xu ZP, Sun ZQ, Zhu B, Wang Q, Zhou J, Jin H, Zhao A, Tang WW, Cao XF. Down-regulation of circPVRL3 promotes the proliferation and migration of gastric cancer cells. Sci Rep. 2018; 8:10111. https://doi.org/10.1038/s41598-018-27837-9 [PubMed]
• 152. Shen Y, Li C, Zhou L, Huang JA. G protein-coupled oestrogen receptor promotes cell growth of non-small cell lung cancer cells via YAP1/QKI/circNOTCH1/m6A methylated NOTCH1 signalling. J Cell Mol Med. 2021; 25:284–96. https://doi.org/10.1111/jcmm.15997 [PubMed]
• 153. Zhang Z, Zhu H, Hu J. CircRAB11FIP1 promoted autophagy flux of ovarian cancer through DSC1 and miR-129. Cell Death Dis. 2021; 12:219. https://doi.org/10.1038/s41419-021-03486-1 [PubMed]
• 154. Wei W, Sun J, Zhang H, Xiao X, Huang C, Wang L, Zhong H, Jiang Y, Zhang X, Jiang G. Circ0008399 Interaction with WTAP Promotes Assembly and Activity of the m⁶A Methyltransferase Complex and Promotes Cisplatin Resistance in Bladder Cancer. Cancer Res. 2021; 81:6142–56. https://doi.org/10.1158/0008-5472.CAN-21-1518 [PubMed]
• 155. Chi F, Cao Y, Chen Y. Analysis and Validation of circRNA-miRNA Network in Regulating m⁶A RNA Methylation Modulators Reveals CircMAP2K4/miR-139-5p/YTHDF1 Axis Involving the Proliferation of Hepatocellular Carcinoma. Front Oncol. 2021; 11:560506. https://doi.org/10.3389/fonc.2021.560506 [PubMed]
• 156. Mo WL, Deng LJ, Cheng Y, Yu WJ, Yang YH, Gu WD. Circular RNA hsa_circ_0072309 promotes tumorigenesis and invasion by regulating the miR-607/FTO axis in non-small cell lung carcinoma. Aging (Albany NY). 2021; 13:11629–45. https://doi.org/10.18632/aging.202856 [PubMed]
• 157. Tang Y, Chen K, Song B, Ma J, Wu X, Xu Q, Wei Z, Su J, Liu G, Rong R, Lu Z, de Magalhães JP, Rigden DJ, Meng J. m6A-Atlas: a comprehensive knowledgebase for unraveling the N6-methyladenosine (m6A) epitranscriptome. Nucleic Acids Res. 2021; 49:D134–43. https://doi.org/10.1093/nar/gkaa692 [PubMed]
• 158. Deng S, Zhang H, Zhu K, Li X, Ye Y, Li R, Liu X, Lin D, Zuo Z, Zheng J. M6A2Target: a comprehensive database for targets of m6A writers, erasers and readers. Brief Bioinform. 2021; 22:bbaa055. https://doi.org/10.1093/bib/bbaa055 [PubMed]
• 159. Luo X, Li H, Liang J, Zhao Q, Xie Y, Ren J, Zuo Z. RMVar: an updated database of functional variants involved in RNA modifications. Nucleic Acids Res. 2021; 49:D1405–12. https://doi.org/10.1093/nar/gkaa811 [PubMed]
• 160. Chen K, Song B, Tang Y, Wei Z, Xu Q, Su J, de Magalhães JP, Rigden DJ, Meng J. RMDisease: a database of genetic variants that affect RNA modifications, with implications for epitranscriptome pathogenesis. Nucleic Acids Res. 2021; 49:D1396–404. https://doi.org/10.1093/nar/gkaa790 [PubMed]
• 161. Liu H, Wang H, Wei Z, Zhang S, Hua G, Zhang SW, Zhang L, Gao SJ, Meng J, Chen X, Huang Y. MeT-DB V2.0: elucidating context-specific functions of N6-methyl-adenosine methyltranscriptome. Nucleic Acids Res. 2018; 46:D281–7. https://doi.org/10.1093/nar/gkx1080 [PubMed]
• 162. Xuan JJ, Sun WJ, Lin PH, Zhou KR, Liu S, Zheng LL, Qu LH, Yang JH. RMBase v2.0: deciphering the map of RNA modifications from epitranscriptome sequencing data. Nucleic Acids Res. 2018; 46:D327–34. https://doi.org/10.1093/nar/gkx934 [PubMed]
• 163. Liu S, Zhu A, He C, Chen M. REPIC: a database for exploring the N⁶-methyladenosine methylome. Genome Biol. 2020; 21:100. https://doi.org/10.1186/s13059-020-02012-4 [PubMed]
• 164. Dominissini D, Moshitch-Moshkovitz S, Schwartz S, Salmon-Divon M, Ungar L, Osenberg S, Cesarkas K, Jacob-Hirsch J, Amariglio N, Kupiec M, Sorek R, Rechavi G. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature. 2012; 485:201–6. https://doi.org/10.1038/nature11112 [PubMed]
• 165. Parker MT, Knop K, Sherwood AV, Schurch NJ, Mackinnon K, Gould PD, Hall AJ, Barton GJ, Simpson GG. Nanopore direct RNA sequencing maps the complexity of Arabidopsis mRNA processing and m⁶A modification. Elife. 2020; 9:e49658. https://doi.org/10.7554/eLife.49658 [PubMed]
• 166. Gao Y, Liu X, Wu B, Wang H, Xi F, Kohnen MV, Reddy ASN, Gu L. Quantitative profiling of N⁶-methyladenosine at single-base resolution in stem-differentiating xylem of Populus trichocarpa using Nanopore direct RNA sequencing. Genome Biol. 2021; 22:22. https://doi.org/10.1186/s13059-020-02241-7 [PubMed]
• 167. Dominissini D, Moshitch-Moshkovitz S, Amariglio N, Rechavi G. Transcriptome-Wide Mapping of N⁶-Methyladenosine by m⁶A-Seq. Methods Enzymol. 2015; 560:131–47. https://doi.org/10.1016/bs.mie.2015.03.001 [PubMed]
• 168. Chen K, Lu Z, Wang X, Fu Y, Luo GZ, Liu N, Han D, Dominissini D, Dai Q, Pan T, He C. High-resolution N(6) -methyladenosine (m(6) A) map using photo-crosslinking-assisted m(6) A sequencing. Angew Chem Int Ed Engl. 2015; 54:1587–90. https://doi.org/10.1002/anie.201410647 [PubMed]
• 169. Linder B, Grozhik AV, Olarerin-George AO, Meydan C, Mason CE, Jaffrey SR. Single-nucleotide-resolution mapping of m6A and m6Am throughout the transcriptome. Nat Methods. 2015; 12:767–72. https://doi.org/10.1038/nmeth.3453 [PubMed]
• 170. Zhang Z, Chen LQ, Zhao YL, Yang CG, Roundtree IA, Zhang Z, Ren J, Xie W, He C, Luo GZ. Single-base mapping of m⁶A by an antibody-independent method. Sci Adv. 2019; 5:eaax0250. https://doi.org/10.1126/sciadv.aax0250 [PubMed]
• 171. Meyer KD. DART-seq: an antibody-free method for global m⁶A detection. Nat Methods. 2019; 16:1275–80. https://doi.org/10.1038/s41592-019-0570-0 [PubMed]
• 172. Shu X, Cao J, Cheng M, Xiang S, Gao M, Li T, Ying X, Wang F, Yue Y, Lu Z, Dai Q, Cui X, Ma L, et al. A metabolic labeling method detects m⁶A transcriptome-wide at single base resolution. Nat Chem Biol. 2020; 16:887–95. https://doi.org/10.1038/s41589-020-0526-9 [PubMed]
• 173. Wang Y, Xiao Y, Dong S, Yu Q, Jia G. Antibody-free enzyme-assisted chemical approach for detection of N⁶-methyladenosine. Nat Chem Biol. 2020; 16:896–903. https://doi.org/10.1038/s41589-020-0525-x [PubMed]
• 174. Dierks D, Garcia-Campos MA, Uzonyi A, Safra M, Edelheit S, Rossi A, Sideri T, Varier RA, Brandis A, Stelzer Y, van Werven F, Scherz-Shouval R, Schwartz S. Multiplexed profiling facilitates robust m6A quantification at site, gene and sample resolution. Nat Methods. 2021; 18:1060–7. https://doi.org/10.1038/s41592-021-01242-z [PubMed]
• 175. Körtel N, Rücklé C, Zhou Y, Busch A, Hoch-Kraft P, Sutandy FXR, Haase J, Pradhan M, Musheev M, Ostareck D, Ostareck-Lederer A, Dieterich C, Hüttelmaier S, et al. Deep and accurate detection of m6A RNA modifications using miCLIP2 and m6Aboost machine learning. Nucleic Acids Res. 2021; 49:e92. https://doi.org/10.1093/nar/gkab485 [PubMed]
• 176. Molinie B, Wang J, Lim KS, Hillebrand R, Lu ZX, Van Wittenberghe N, Howard BD, Daneshvar K, Mullen AC, Dedon P, Xing Y, Giallourakis CC. m(6)A-LAIC-seq reveals the census and complexity of the m(6)A epitranscriptome. Nat Methods. 2016; 13:692–8. https://doi.org/10.1038/nmeth.3898 [PubMed]
• 177. Xiao Y, Wang Y, Tang Q, Wei L, Zhang X, Jia G. An Elongation- and Ligation-Based qPCR Amplification Method for the Radiolabeling-Free Detection of Locus-Specific N⁶ -Methyladenosine Modification. Angew Chem Int Ed Engl. 2018; 57:15995–6000. https://doi.org/10.1002/anie.201807942 [PubMed]
• 178. Liu N, Parisien M, Dai Q, Zheng G, He C, Pan T. Probing N6-methyladenosine RNA modification status at single nucleotide resolution in mRNA and long noncoding RNA. RNA. 2013; 19:1848–56. https://doi.org/10.1261/rna.041178.113 [PubMed]
• 179. Liu C, Sun H, Yi Y, Shen W, Li K, Xiao Y, Li F, Li Y, Hou Y, Lu B, Liu W, Meng H, Peng J, et al. Absolute quantification of single-base m⁶A methylation in the mammalian transcriptome using GLORI. Nat Biotechnol. 2023; 41:355–66. https://doi.org/10.1038/s41587-022-01487-9 [PubMed]
• 180. Deng X, Chen K, Luo GZ, Weng X, Ji Q, Zhou T, He C. Widespread occurrence of N6-methyladenosine in bacterial mRNA. Nucleic Acids Res. 2015; 43:6557–67. https://doi.org/10.1093/nar/gkv596 [PubMed]
• 181. Hafner M, Landthaler M, Burger L, Khorshid M, Hausser J, Berninger P, Rothballer A, Ascano M Jr, Jungkamp AC, Munschauer M, Ulrich A, Wardle GS, Dewell S, et al. Transcriptome-wide identification of RNA-binding protein and microRNA target sites by PAR-CLIP. Cell. 2010; 141:129–41. https://doi.org/10.1016/j.cell.2010.03.009 [PubMed]
• 182. Yin HS, Zhou YL, Yang ZQ, Guo YL, Wang XX, Ai SY, Zhang XS. Electrochemical immunosensor for N6-methyladenosine RNA modification detection. Sensor Actuat B-Chem. 2015; 221:1–6. https://doi.org/10.1016/j.snb.2015.06.045
• 183. Jiang X, Liu B, Nie Z, Duan L, Xiong Q, Jin Z, Yang C, Chen Y. The role of m6A modification in the biological functions and diseases. Signal Transduct Target Ther. 2021; 6:74. https://doi.org/10.1038/s41392-020-00450-x [PubMed]
• 184. Tong J, Flavell RA, Li HB. RNA m⁶A modification and its function in diseases. Front Med. 2018; 12:481–9. https://doi.org/10.1007/s11684-018-0654-8 [PubMed]
• 185. Wen J, Lv R, Ma H, Shen H, He C, Wang J, Jiao F, Liu H, Yang P, Tan L, Lan F, Shi YG, He C, et al. Zc3h13 Regulates Nuclear RNA m⁶A Methylation and Mouse Embryonic Stem Cell Self-Renewal. Mol Cell. 2018; 69:1028–38.e6. https://doi.org/10.1016/j.molcel.2018.02.015 [PubMed]
• 186. Wojtas MN, Pandey RR, Mendel M, Homolka D, Sachidanandam R, Pillai RS. Regulation of m⁶A Transcripts by the 3'→5' RNA Helicase YTHDC2 Is Essential for a Successful Meiotic Program in the Mammalian Germline. Mol Cell. 2017; 68:374–87.e12. https://doi.org/10.1016/j.molcel.2017.09.021 [PubMed]
• 187. Liu N, Zhou KI, Parisien M, Dai Q, Diatchenko L, Pan T. N6-methyladenosine alters RNA structure to regulate binding of a low-complexity protein. Nucleic Acids Res. 2017; 45:6051–63. https://doi.org/10.1093/nar/gkx141 [PubMed]
• 188. Liu N, Dai Q, Zheng G, He C, Parisien M, Pan T. N(6)-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions. Nature. 2015; 518:560–4. https://doi.org/10.1038/nature14234 [PubMed]
• 189. Vu LP, Pickering BF, Cheng Y, Zaccara S, Nguyen D, Minuesa G, Chou T, Chow A, Saletore Y, MacKay M, Schulman J, Famulare C, Patel M, et al. The N⁶-methyladenosine (m⁶A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells. Nat Med. 2017; 23:1369–76. https://doi.org/10.1038/nm.4416 [PubMed]
• 190. Lin S, Choe J, Du P, Triboulet R, Gregory RI. The m⁶A Methyltransferase METTL3 Promotes Translation in Human Cancer Cells. Mol Cell. 2016; 62:335–45. https://doi.org/10.1016/j.molcel.2016.03.021 [PubMed]
• 191. Xu H, Wang H, Zhao W, Fu S, Li Y, Ni W, Xin Y, Li W, Yang C, Bai Y, Zhan M, Lu L. SUMO1 modification of methyltransferase-like 3 promotes tumor progression via regulating Snail mRNA homeostasis in hepatocellular carcinoma. Theranostics. 2020; 10:5671–86. https://doi.org/10.7150/thno.42539 [PubMed]
• 192. Liu J, Eckert MA, Harada BT, Liu SM, Lu Z, Yu K, Tienda SM, Chryplewicz A, Zhu AC, Yang Y, Huang JT, Chen SM, Xu ZG, et al. m⁶A mRNA methylation regulates AKT activity to promote the proliferation and tumorigenicity of endometrial cancer. Nat Cell Biol. 2018; 20:1074–83. https://doi.org/10.1038/s41556-018-0174-4 [PubMed]
• 193. Wang M, Liu J, Zhao Y, He R, Xu X, Guo X, Li X, Xu S, Miao J, Guo J, Zhang H, Gong J, Zhu F, et al. Upregulation of METTL14 mediates the elevation of PERP mRNA N⁶ adenosine methylation promoting the growth and metastasis of pancreatic cancer. Mol Cancer. 2020; 19:130. https://doi.org/10.1186/s12943-020-01249-8 [PubMed]
• 194. Li F, Yi Y, Miao Y, Long W, Long T, Chen S, Cheng W, Zou C, Zheng Y, Wu X, Ding J, Zhu K, Chen D, et al. N⁶-Methyladenosine Modulates Nonsense-Mediated mRNA Decay in Human Glioblastoma. Cancer Res. 2019; 79:5785–98. https://doi.org/10.1158/0008-5472.CAN-18-2868 [PubMed]
• 195. Tassinari V, Cesarini V, Tomaselli S, Ianniello Z, Silvestris DA, Ginistrelli LC, Martini M, De Angelis B, De Luca G, Vitiani LR, Fatica A, Locatelli F, Gallo A. ADAR1 is a new target of METTL3 and plays a pro-oncogenic role in glioblastoma by an editing-independent mechanism. Genome Biol. 2021; 22:51. https://doi.org/10.1186/s13059-021-02271-9 [PubMed]
• 196. Hua W, Zhao Y, Jin X, Yu D, He J, Xie D, Duan P. METTL3 promotes ovarian carcinoma growth and invasion through the regulation of AXL translation and epithelial to mesenchymal transition. Gynecol Oncol. 2018; 151:356–65. https://doi.org/10.1016/j.ygyno.2018.09.015 [PubMed]
• 197. Ying X, Jiang X, Zhang H, Liu B, Huang Y, Zhu X, Qi D, Yuan G, Luo J, Ji W. Programmable N6-methyladenosine modification of CDCP1 mRNA by RCas9-methyltransferase like 3 conjugates promotes bladder cancer development. Mol Cancer. 2020; 19:169. https://doi.org/10.1186/s12943-020-01289-0 [PubMed]
• 198. Cai X, Wang X, Cao C, Gao Y, Zhang S, Yang Z, Liu Y, Zhang X, Zhang W, Ye L. HBXIP-elevated methyltransferase METTL3 promotes the progression of breast cancer via inhibiting tumor suppressor let-7g. Cancer Lett. 2018; 415:11–9. https://doi.org/10.1016/j.canlet.2017.11.018 [PubMed]
• 199. Zhang C, Samanta D, Lu H, Bullen JW, Zhang H, Chen I, He X, Semenza GL. Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m⁶A-demethylation of NANOG mRNA. Proc Natl Acad Sci U S A. 2016; 113:E2047–56. https://doi.org/10.1073/pnas.1602883113 [PubMed]
• 200. Miao W, Chen J, Jia L, Ma J, Song D. The m6A methyltransferase METTL3 promotes osteosarcoma progression by regulating the m6A level of LEF1. Biochem Biophys Res Commun. 2019; 516:719–25. https://doi.org/10.1016/j.bbrc.2019.06.128 [PubMed]
• 201. Li J, Xie H, Ying Y, Chen H, Yan H, He L, Xu M, Xu X, Liang Z, Liu B, Wang X, Zheng X, Xie L. YTHDF2 mediates the mRNA degradation of the tumor suppressors to induce AKT phosphorylation in N6-methyladenosine-dependent way in prostate cancer. Mol Cancer. 2020; 19:152. https://doi.org/10.1186/s12943-020-01267-6 [PubMed]
• 202. Wang H, Wei W, Zhang ZY, Liu Y, Shi B, Zhong W, Zhang HS, Fang X, Sun CL, Wang JB, Liu LX. TCF4 and HuR mediated-METTL14 suppresses dissemination of colorectal cancer via N6-methyladenosine-dependent silencing of ARRDC4. Cell Death Dis. 2021; 13:3. https://doi.org/10.1038/s41419-021-04459-0 [PubMed]
• 203. Wang K, Jiang L, Zhang Y, Chen C. Progression of Thyroid Carcinoma Is Promoted by the m6A Methyltransferase METTL3 Through Regulating m⁶A Methylation on TCF1. Onco Targets Ther. 2020; 13:1605–12. https://doi.org/10.2147/OTT.S234751 [PubMed]
• 204. Xie JW, Huang XB, Chen QY, Ma YB, Zhao YJ, Liu LC, Wang JB, Lin JX, Lu J, Cao LL, Lin M, Tu RH, Zheng CH, et al. m⁶A modification-mediated BATF2 acts as a tumor suppressor in gastric cancer through inhibition of ERK signaling. Mol Cancer. 2020; 19:114. https://doi.org/10.1186/s12943-020-01223-4 [PubMed]
• 205. Gong D, Zhang J, Chen Y, Xu Y, Ma J, Hu G, Huang Y, Zheng J, Zhai W, Xue W. The m⁶A-suppressed P2RX6 activation promotes renal cancer cells migration and invasion through ATP-induced Ca²⁺ influx modulating ERK1/2 phosphorylation and MMP9 signaling pathway. J Exp Clin Cancer Res. 2019; 38:233. https://doi.org/10.1186/s13046-019-1223-y [PubMed]
• 206. Zhang P, He Q, Lei Y, Li Y, Wen X, Hong M, Zhang J, Ren X, Wang Y, Yang X, He Q, Ma J, Liu N. m⁶A-mediated ZNF750 repression facilitates nasopharyngeal carcinoma progression. Cell Death Dis. 2018; 9:1169. https://doi.org/10.1038/s41419-018-1224-3 [PubMed]
• 207. Chen S, Li Y, Zhi S, Ding Z, Wang W, Peng Y, Huang Y, Zheng R, Yu H, Wang J, Hu M, Miao J, Li J. WTAP promotes osteosarcoma tumorigenesis by repressing HMBOX1 expression in an m⁶A-dependent manner. Cell Death Dis. 2020; 11:659. https://doi.org/10.1038/s41419-020-02847-6 [PubMed]
• 208. Wang X, Tian L, Li Y, Wang J, Yan B, Yang L, Li Q, Zhao R, Liu M, Wang P, Sun Y. RBM15 facilitates laryngeal squamous cell carcinoma progression by regulating TMBIM6 stability through IGF2BP3 dependent. J Exp Clin Cancer Res. 2021; 40:80. https://doi.org/10.1186/s13046-021-01871-4 [PubMed]
• 209. Zhuang C, Zhuang C, Luo X, Huang X, Yao L, Li J, Li Y, Xiong T, Ye J, Zhang F, Gui Y. N6-methyladenosine demethylase FTO suppresses clear cell renal cell carcinoma through a novel FTO-PGC-1α signalling axis. J Cell Mol Med. 2019; 23:2163–73. https://doi.org/10.1111/jcmm.14128 [PubMed]
• 210. Zhou S, Bai ZL, Xia D, Zhao ZJ, Zhao R, Wang YY, Zhe H. FTO regulates the chemo-radiotherapy resistance of cervical squamous cell carcinoma (CSCC) by targeting β-catenin through mRNA demethylation. Mol Carcinog. 2018; 57:590–7. https://doi.org/10.1002/mc.22782 [PubMed]
• 211. Liu J, Ren D, Du Z, Wang H, Zhang H, Jin Y. m⁶A demethylase FTO facilitates tumor progression in lung squamous cell carcinoma by regulating MZF1 expression. Biochem Biophys Res Commun. 2018; 502:456–64. https://doi.org/10.1016/j.bbrc.2018.05.175 [PubMed]
• 212. Li J, Zhu L, Shi Y, Liu J, Lin L, Chen X. m6A demethylase FTO promotes hepatocellular carcinoma tumorigenesis via mediating PKM2 demethylation. Am J Transl Res. 2019; 11:6084–92. [PubMed]
• 213. Zheng X, Gong Y. Functions of RNA N⁶-methyladenosine modification in acute myeloid leukemia. Biomark Res. 2021; 9:36. https://doi.org/10.1186/s40364-021-00293-w [PubMed]
• 214. Jiang Y, Wan Y, Gong M, Zhou S, Qiu J, Cheng W. RNA demethylase ALKBH5 promotes ovarian carcinogenesis in a simulated tumour microenvironment through stimulating NF-κB pathway. J Cell Mol Med. 2020; 24:6137–48. https://doi.org/10.1111/jcmm.15228 [PubMed]
• 215. Guo X, Li K, Jiang W, Hu Y, Xiao W, Huang Y, Feng Y, Pan Q, Wan R. RNA demethylase ALKBH5 prevents pancreatic cancer progression by posttranscriptional activation of PER1 in an m6A-YTHDF2-dependent manner. Mol Cancer. 2020; 19:91. https://doi.org/10.1186/s12943-020-01158-w [PubMed]
• 216. Guo J, Wu Y, Du J, Yang L, Chen W, Gong K, Dai J, Miao S, Jin D, Xi S. Deregulation of UBE2C-mediated autophagy repression aggravates NSCLC progression. Oncogenesis. 2018; 7:49. https://doi.org/10.1038/s41389-018-0054-6 [PubMed]
• 217. Zhu Z, Qian Q, Zhao X, Ma L, Chen P. N⁶-methyladenosine ALKBH5 promotes non-small cell lung cancer progress by regulating TIMP3 stability. Gene. 2020; 731:144348. https://doi.org/10.1016/j.gene.2020.144348 [PubMed]
• 218. Ma L, Chen T, Zhang X, Miao Y, Tian X, Yu K, Xu X, Niu Y, Guo S, Zhang C, Qiu S, Qiao Y, Fang W, et al. The m⁶A reader YTHDC2 inhibits lung adenocarcinoma tumorigenesis by suppressing SLC7A11-dependent antioxidant function. Redox Biol. 2021; 38:101801. https://doi.org/10.1016/j.redox.2020.101801 [PubMed]
• 219. Pi J, Wang W, Ji M, Wang X, Wei X, Jin J, Liu T, Qiang J, Qi Z, Li F, Liu Y, Ma Y, Si Y, et al. YTHDF1 Promotes Gastric Carcinogenesis by Controlling Translation of FZD7. Cancer Res. 2021; 81:2651–65. https://doi.org/10.1158/0008-5472.CAN-20-0066 [PubMed]
• 220. Liu T, Wei Q, Jin J, Luo Q, Liu Y, Yang Y, Cheng C, Li L, Pi J, Si Y, Xiao H, Li L, Rao S, et al. The m6A reader YTHDF1 promotes ovarian cancer progression via augmenting EIF3C translation. Nucleic Acids Res. 2020; 48:3816–31. https://doi.org/10.1093/nar/gkaa048 [PubMed]
• 221. Dixit D, Prager BC, Gimple RC, Poh HX, Wang Y, Wu Q, Qiu Z, Kidwell RL, Kim LJY, Xie Q, Vitting-Seerup K, Bhargava S, Dong Z, et al. The RNA m6A Reader YTHDF2 Maintains Oncogene Expression and Is a Targetable Dependency in Glioblastoma Stem Cells. Cancer Discov. 2021; 11:480–99. https://doi.org/10.1158/2159-8290.CD-20-0331 [PubMed]
• 222. Chai RC, Chang YZ, Chang X, Pang B, An SY, Zhang KN, Chang YH, Jiang T, Wang YZ. YTHDF2 facilitates UBXN1 mRNA decay by recognizing METTL3-mediated m⁶A modification to activate NF-κB and promote the malignant progression of glioma. J Hematol Oncol. 2021; 14:109. https://doi.org/10.1186/s13045-021-01124-z [PubMed]
• 223. Xu F, Li J, Ni M, Cheng J, Zhao H, Wang S, Zhou X, Wu X. FBW7 suppresses ovarian cancer development by targeting the N⁶-methyladenosine binding protein YTHDF2. Mol Cancer. 2021; 20:45. https://doi.org/10.1186/s12943-021-01340-8 [PubMed]
• 224. Zhang C, Huang S, Zhuang H, Ruan S, Zhou Z, Huang K, Ji F, Ma Z, Hou B, He X. YTHDF2 promotes the liver cancer stem cell phenotype and cancer metastasis by regulating OCT4 expression via m6A RNA methylation. Oncogene. 2020; 39:4507–18. https://doi.org/10.1038/s41388-020-1303-7 [PubMed]
• 225. Müller S, Glaß M, Singh AK, Haase J, Bley N, Fuchs T, Lederer M, Dahl A, Huang H, Chen J, Posern G, Hüttelmaier S. IGF2BP1 promotes SRF-dependent transcription in cancer in a m6A- and miRNA-dependent manner. Nucleic Acids Res. 2019; 47:375–90. https://doi.org/10.1093/nar/gky1012 [PubMed]
• 226. Pu J, Wang J, Qin Z, Wang A, Zhang Y, Wu X, Wu Y, Li W, Xu Z, Lu Y, Tang Q, Wei H. IGF2BP2 Promotes Liver Cancer Growth Through an m6A-FEN1-Dependent Mechanism. Front Oncol. 2020; 10:578816. https://doi.org/10.3389/fonc.2020.578816 [PubMed]
• 227. Xue T, Liu X, Zhang M, E Q, Liu S, Zou M, Li Y, Ma Z, Han Y, Thompson P, Zhang X. PADI2-Catalyzed MEK1 Citrullination Activates ERK1/2 and Promotes IGF2BP1-Mediated SOX2 mRNA Stability in Endometrial Cancer. Adv Sci (Weinh). 2021; 8:2002831. https://doi.org/10.1002/advs.202002831 [PubMed]
• 228. Liu X, Su K, Sun X, Jiang Y, Wang L, Hu C, Zhang C, Lu M, Du X, Xing B. Sec62 promotes stemness and chemoresistance of human colorectal cancer through activating Wnt/β-catenin pathway. J Exp Clin Cancer Res. 2021; 40:132. https://doi.org/10.1186/s13046-021-01934-6 [PubMed]
• 229. Regué L, Zhao L, Ji F, Wang H, Avruch J, Dai N. RNA m6A reader IMP2/IGF2BP2 promotes pancreatic β-cell proliferation and insulin secretion by enhancing PDX1 expression. Mol Metab. 2021; 48:101209. https://doi.org/10.1016/j.molmet.2021.101209 [PubMed]
• 230. Yang Z, Wang T, Wu D, Min Z, Tan J, Yu B. RNA N6-methyladenosine reader IGF2BP3 regulates cell cycle and angiogenesis in colon cancer. J Exp Clin Cancer Res. 2020; 39:203. https://doi.org/10.1186/s13046-020-01714-8 [PubMed]
• 231. Dahal U, Le K, Gupta M. RNA m6A methyltransferase METTL3 regulates invasiveness of melanoma cells by matrix metallopeptidase 2. Melanoma Res. 2019; 29:382–9. https://doi.org/10.1097/CMR.0000000000000580 [PubMed]
• 232. Jiang F, Tang X, Tang C, Hua Z, Ke M, Wang C, Zhao J, Gao S, Jurczyszyn A, Janz S, Beksac M, Zhan F, Gu C, Yang Y. HNRNPA2B1 promotes multiple myeloma progression by increasing AKT3 expression via m6A-dependent stabilization of ILF3 mRNA. J Hematol Oncol. 2021; 14:54. https://doi.org/10.1186/s13045-021-01066-6 [PubMed]
• 233. Bi X, Lv X, Liu D, Guo H, Yao G, Wang L, Liang X, Yang Y. METTL3-mediated maturation of miR-126-5p promotes ovarian cancer progression via PTEN-mediated PI3K/Akt/mTOR pathway. Cancer Gene Ther. 2021; 28:335–49. https://doi.org/10.1038/s41417-020-00222-3 [PubMed]
• 234. Pan X, Hong X, Li S, Meng P, Xiao F. METTL3 promotes adriamycin resistance in MCF-7 breast cancer cells by accelerating pri-microRNA-221-3p maturation in a m6A-dependent manner. Exp Mol Med. 2021; 53:91–102. https://doi.org/10.1038/s12276-020-00510-w [PubMed]
• 235. He H, Wu W, Sun Z, Chai L. MiR-4429 prevented gastric cancer progression through targeting METTL3 to inhibit m⁶A-caused stabilization of SEC62. Biochem Biophys Res Commun. 2019; 517:581–7. https://doi.org/10.1016/j.bbrc.2019.07.058 [PubMed]
• 236. Du M, Zhang Y, Mao Y, Mou J, Zhao J, Xue Q, Wang D, Huang J, Gao S, Gao Y. MiR-33a suppresses proliferation of NSCLC cells via targeting METTL3 mRNA. Biochem Biophys Res Commun. 2017; 482:582–9. https://doi.org/10.1016/j.bbrc.2016.11.077 [PubMed]
• 237. Wei W, Huo B, Shi X. miR-600 inhibits lung cancer via downregulating the expression of METTL3. Cancer Manag Res. 2019; 11:1177–87. https://doi.org/10.2147/CMAR.S181058 [PubMed]
• 238. Cui X, Wang Z, Li J, Zhu J, Ren Z, Zhang D, Zhao W, Fan Y, Zhang D, Sun R. Cross talk between RNA N6-methyladenosine methyltransferase-like 3 and miR-186 regulates hepatoblastoma progression through Wnt/β-catenin signalling pathway. Cell Prolif. 2020; 53:e12768. https://doi.org/10.1111/cpr.12768 [PubMed]
• 239. Yue C, Chen J, Li Z, Li L, Chen J, Guo Y. microRNA-96 promotes occurrence and progression of colorectal cancer via regulation of the AMPKα2-FTO-m6A/MYC axis. J Exp Clin Cancer Res. 2020; 39:240. https://doi.org/10.1186/s13046-020-01731-7 [PubMed]
• 240. Shen XP, Ling X, Lu H, Zhou CX, Zhang JK, Yu Q. Low expression of microRNA-1266 promotes colorectal cancer progression via targeting FTO. Eur Rev Med Pharmacol Sci. 2018; 22:8220–6. https://doi.org/10.26355/eurrev_201812_16516 [PubMed]
• 241. Kleemann M, Schneider H, Unger K, Sander P, Schneider EM, Fischer-Posovszky P, Handrick R, Otte K. MiR-744-5p inducing cell death by directly targeting HNRNPC and NFIX in ovarian cancer cells. Sci Rep. 2018; 8:9020. https://doi.org/10.1038/s41598-018-27438-6 [PubMed]
• 242. Xu C, Yuan B, He T, Ding B, Li S. Prognostic values of YTHDF1 regulated negatively by mir-3436 in Glioma. J Cell Mol Med. 2020; 24:7538–49. https://doi.org/10.1111/jcmm.15382 [PubMed]
• 243. Yao FY, Zhao C, Zhong FM, Qin TY, Wen F, Li MY, Liu J, Huang B, Wang XZ. m⁶A Modification of lncRNA NEAT1 Regulates Chronic Myelocytic Leukemia Progression via miR-766-5p/CDKN1A Axis. Front Oncol. 2021; 11:679634. https://doi.org/10.3389/fonc.2021.679634 [PubMed]
• 244. Rong D, Dong Q, Qu H, Deng X, Gao F, Li Q, Sun P. m⁶A-induced LINC00958 promotes breast cancer tumorigenesis via the miR-378a-3p/YY1 axis. Cell Death Discov. 2021; 7:27. https://doi.org/10.1038/s41420-020-00382-z [PubMed]
• 245. Liu T, Wang H, Fu Z, Wang Z, Wang J, Gan X, Wang A, Wang L. Methyltransferase-like 14 suppresses growth and metastasis of renal cell carcinoma by decreasing long noncoding RNA NEAT1. Cancer Sci. 2022; 113:446–58. https://doi.org/10.1111/cas.15212 [PubMed]
• 246. Guo T, Liu DF, Peng SH, Xu AM. ALKBH5 promotes colon cancer progression by decreasing methylation of the lncRNA NEAT1. Am J Transl Res. 2020; 12:4542–9. [PubMed]
• 247. Ban Y, Tan P, Cai J, Li J, Hu M, Zhou Y, Mei Y, Tan Y, Li X, Zeng Z, Xiong W, Li G, Li X, et al. LNCAROD is stabilized by m6A methylation and promotes cancer progression via forming a ternary complex with HSPA1A and YBX1 in head and neck squamous cell carcinoma. Mol Oncol. 2020; 14:1282–96. https://doi.org/10.1002/1878-0261.12676 [PubMed]
• 248. Ji F, Lu Y, Chen S, Lin X, Yu Y, Zhu Y, Luo X. m⁶A methyltransferase METTL3-mediated lncRNA FOXD2-AS1 promotes the tumorigenesis of cervical cancer. Mol Ther Oncolytics. 2021; 22:574–81. https://doi.org/10.1016/j.omto.2021.07.004 [PubMed]
• 249. Liu HT, Zou YX, Zhu WJ, Sen-Liu, Zhang GH, Ma RR, Guo XY, Gao P. lncRNA THAP7-AS1, transcriptionally activated by SP1 and post-transcriptionally stabilized by METTL3-mediated m6A modification, exerts oncogenic properties by improving CUL4B entry into the nucleus. Cell Death Differ. 2022; 29:627–41. https://doi.org/10.1038/s41418-021-00879-9 [PubMed]
• 250. Wu J, Pang R, Li M, Chen B, Huang J, Zhu Y. m6A-Induced LncRNA MEG3 Suppresses the Proliferation, Migration and Invasion of Hepatocellular Carcinoma Cell Through miR-544b/BTG2 Signaling. Onco Targets Ther. 2021; 14:3745–55. https://doi.org/10.2147/OTT.S289198 [PubMed]
• 251. Lang C, Yin C, Lin K, Li Y, Yang Q, Wu Z, Du H, Ren D, Dai Y, Peng X. m⁶ A modification of lncRNA PCAT6 promotes bone metastasis in prostate cancer through IGF2BP2-mediated IGF1R mRNA stabilization. Clin Transl Med. 2021; 11:e426. https://doi.org/10.1002/ctm2.426 [PubMed]
• 252. Qian X, Yang J, Qiu Q, Li X, Jiang C, Li J, Dong L, Ying K, Lu B, Chen E, Liu P, Lu Y. LCAT3, a novel m6A-regulated long non-coding RNA, plays an oncogenic role in lung cancer via binding with FUBP1 to activate c-MYC. J Hematol Oncol. 2021; 14:112. https://doi.org/10.1186/s13045-021-01123-0 [PubMed]
• 253. Shen D, Ding L, Lu Z, Wang R, Yu C, Wang H, Zheng Q, Wang X, Xu W, Yu H, Xu L, Wang M, Yu S, et al. METTL14-mediated Lnc-LSG1 m6A modification inhibits clear cell renal cell carcinoma metastasis via regulating ESRP2 ubiquitination. Mol Ther Nucleic Acids. 2021; 27:547–61. https://doi.org/10.1016/j.omtn.2021.12.024 [PubMed]
• 254. Zhang X, Li D, Jia C, Cai H, Lv Z, Wu B. METTL14 promotes tumorigenesis by regulating lncRNA OIP5-AS1/miR-98/ADAMTS8 signaling in papillary thyroid cancer. Cell Death Dis. 2021; 12:617. https://doi.org/10.1038/s41419-021-03891-6 [PubMed]
• 255. Sun T, Wu Z, Wang X, Wang Y, Hu X, Qin W, Lu S, Xu D, Wu Y, Chen Q, Ding X, Guo H, Li Y, et al. LNC942 promoting METTL14-mediated m⁶A methylation in breast cancer cell proliferation and progression. Oncogene. 2020; 39:5358–72. https://doi.org/10.1038/s41388-020-1338-9 [PubMed]
• 256. Wang J, Zha J, Wang X. Knockdown of lncRNA NUTM2A-AS1 inhibits lung adenocarcinoma cell viability by regulating the miR-590-5p/METTL3 axis. Oncol Lett. 2021; 22:798. https://doi.org/10.3892/ol.2021.13059 [PubMed]
• 257. Wang G, Zhang Z, Xia C. Long non-coding RNA LINC00240 promotes gastric cancer progression via modulating miR-338-5p/METTL3 axis. Bioengineered. 2021; 12:9678–91. https://doi.org/10.1080/21655979.2021.1983276 [PubMed]
• 258. Hu H, Kong Q, Huang XX, Zhang HR, Hu KF, Jing Y, Jiang YF, Peng Y, Wu LC, Fu QS, Xu L, Xia YB. Longnon-coding RNA BLACAT2 promotes gastric cancer progression via the miR-193b-5p/METTL3 pathway. J Cancer. 2021; 12:3209–21. https://doi.org/10.7150/jca.50403 [PubMed]
• 259. Bo C, Li N, He L, Zhang S, An Y. Long non-coding RNA ILF3-AS1 facilitates hepatocellular carcinoma progression by stabilizing ILF3 mRNA in an m⁶A-dependent manner. Hum Cell. 2021; 34:1843–54. https://doi.org/10.1007/s13577-021-00608-x [PubMed]
• 260. Wang X, Zhang J, Wang Y. Long noncoding RNA GAS5-AS1 suppresses growth and metastasis of cervical cancer by increasing GAS5 stability. Am J Transl Res. 2019; 11:4909–21. [PubMed]
• 261. Tang S, Liu Q, Xu M. LINC00857 promotes cell proliferation and migration in colorectal cancer by interacting with YTHDC1 and stabilizing SLC7A5. Oncol Lett. 2021; 22:578. https://doi.org/10.3892/ol.2021.12839 [PubMed]
• 262. Wang C, Gu Y, Zhang E, Zhang K, Qin N, Dai J, Zhu M, Liu J, Xie K, Jiang Y, Guo X, Liu M, Jin G, et al. A cancer-testis non-coding RNA LIN28B-AS1 activates driver gene LIN28B by interacting with IGF2BP1 in lung adenocarcinoma. Oncogene. 2019; 38:1611–24. https://doi.org/10.1038/s41388-018-0548-x [PubMed]
• 263. Wang H, Liang L, Dong Q, Huan L, He J, Li B, Yang C, Jin H, Wei L, Yu C, Zhao F, Li J, Yao M, et al. Long noncoding RNA miR503HG, a prognostic indicator, inhibits tumor metastasis by regulating the HNRNPA2B1/NF-κB pathway in hepatocellular carcinoma. Theranostics. 2018; 8:2814–29. https://doi.org/10.7150/thno.23012 [PubMed]
• 264. Gu Y, Niu S, Wang Y, Duan L, Pan Y, Tong Z, Zhang X, Yang Z, Peng B, Wang X, Han X, Li Y, Cheng T, et al. DMDRMR-Mediated Regulation of m⁶A-Modified CDK4 by m⁶A Reader IGF2BP3 Drives ccRCC Progression. Cancer Res. 2021; 81:923–34. https://doi.org/10.1158/0008-5472.CAN-20-1619 [PubMed]
• 265. Chen Z, Chen X, Lei T, Gu Y, Gu J, Huang J, Lu B, Yuan L, Sun M, Wang Z. Integrative Analysis of NSCLC Identifies LINC01234 as an Oncogenic lncRNA that Interacts with HNRNPA2B1 and Regulates miR-106b Biogenesis. Mol Ther. 2020; 28:1479–93. https://doi.org/10.1016/j.ymthe.2020.03.010 [PubMed]
• 266. Xu J, Wan Z, Tang M, Lin Z, Jiang S, Ji L, Gorshkov K, Mao Q, Xia S, Cen D, Zheng J, Liang X, Cai X. N⁶-methyladenosine-modified CircRNA-SORE sustains sorafenib resistance in hepatocellular carcinoma by regulating β-catenin signaling. Mol Cancer. 2020; 19:163. https://doi.org/10.1186/s12943-020-01281-8 [PubMed]
• 267. Wang T, Liu Z, She Y, Deng J, Zhong Y, Zhao M, Li S, Xie D, Sun X, Hu X, Chen C. A novel protein encoded by circASK1 ameliorates gefitinib resistance in lung adenocarcinoma by competitively activating ASK1-dependent apoptosis. Cancer Lett. 2021; 520:321–31. https://doi.org/10.1016/j.canlet.2021.08.007 [PubMed]
• 268. Wu P, Fang X, Liu Y, Tang Y, Wang W, Li X, Fan Y. N6-methyladenosine modification of circCUX1 confers radioresistance of hypopharyngeal squamous cell carcinoma through caspase1 pathway. Cell Death Dis. 2021; 12:298. https://doi.org/10.1038/s41419-021-03558-2 [PubMed]
• 269. Wang M, Yang Y, Yang J, Yang J, Han S. circ_KIAA1429 accelerates hepatocellular carcinoma advancement through the mechanism of m⁶A-YTHDF3-Zeb1. Life Sci. 2020; 257:118082. https://doi.org/10.1016/j.lfs.2020.118082 [PubMed]
• 270. Jiang X, Xing L, Chen Y, Qin R, Song S, Lu Y, Xie S, Wang L, Pu H, Gui X, Li T, Xu J, Li J, et al. CircMEG3 inhibits telomerase activity by reducing Cbf5 in human liver cancer stem cells. Mol Ther Nucleic Acids. 2020; 23:310–23. https://doi.org/10.1016/j.omtn.2020.11.009 [PubMed]
• 271. Li B, Zhu L, Lu C, Wang C, Wang H, Jin H, Ma X, Cheng Z, Yu C, Wang S, Zuo Q, Zhou Y, Wang J, et al. circNDUFB2 inhibits non-small cell lung cancer progression via destabilizing IGF2BPs and activating anti-tumor immunity. Nat Commun. 2021; 12:295. https://doi.org/10.1038/s41467-020-20527-z [PubMed]
• 272. Xie F, Huang C, Liu F, Zhang H, Xiao X, Sun J, Zhang X, Jiang G. CircPTPRA blocks the recognition of RNA N⁶-methyladenosine through interacting with IGF2BP1 to suppress bladder cancer progression. Mol Cancer. 2021; 20:68. https://doi.org/10.1186/s12943-021-01359-x [PubMed]
• 273. Zheng Y, Nie P, Peng D, He Z, Liu M, Xie Y, Miao Y, Zuo Z, Ren J. m6AVar: a database of functional variants involved in m6A modification. Nucleic Acids Res. 2018; 46:D139–45. https://doi.org/10.1093/nar/gkx895 [PubMed]
• 274. Han Y, Feng J, Xia L, Dong X, Zhang X, Zhang S, Miao Y, Xu Q, Xiao S, Zuo Z, Xia L, He C. CVm6A: A Visualization and Exploration Database for m⁶As in Cell Lines. Cells. 2019; 8:168. https://doi.org/10.3390/cells8020168 [PubMed]
• 275. Wu X, Wei Z, Chen K, Zhang Q, Su J, Liu H, Zhang L, Meng J. m6Acomet: large-scale functional prediction of individual m⁶A RNA methylation sites from an RNA co-methylation network. BMC Bioinformatics. 2019; 20:223. https://doi.org/10.1186/s12859-019-2840-3 [PubMed]
• 276. Zhou D, Wang H, Bi F, Xing J, Gu Y, Wang C, Zhang M, Huang Y, Zeng J, Wu Q, Zhang Y. M6ADD: a comprehensive database of m⁶A modifications in diseases. RNA Biol. 2021; 18:2354–62. https://doi.org/10.1080/15476286.2021.1913302 [PubMed]
• 277. Liu Q, Gregory RI. RNAmod: an integrated system for the annotation of mRNA modifications. Nucleic Acids Res. 2019; 47:W548–55. https://doi.org/10.1093/nar/gkz479 [PubMed]
• 278. Tang Y, Chen K, Wu X, Wei Z, Zhang SY, Song B, Zhang SW, Huang Y, Meng J. DRUM: Inference of Disease-Associated m⁶A RNA Methylation Sites From a Multi-Layer Heterogeneous Network. Front Genet. 2019; 10:266. https://doi.org/10.3389/fgene.2019.00266 [PubMed]
• 279. Nie F, Feng P, Song X, Wu M, Tang Q, Chen W. RNAWRE: a resource of writers, readers and erasers of RNA modifications. Database (Oxford). 2020; 2020:baaa049. https://doi.org/10.1093/database/baaa049 [PubMed]
• 280. Zhou Y, Zeng P, Li YH, Zhang Z, Cui Q. SRAMP: prediction of mammalian N6-methyladenosine (m6A) sites based on sequence-derived features. Nucleic Acids Res. 2016; 44:e91. https://doi.org/10.1093/nar/gkw104 [PubMed]
• 281. Antanaviciute A, Baquero-Perez B, Watson CM, Harrison SM, Lascelles C, Crinnion L, Markham AF, Bonthron DT, Whitehouse A, Carr IM. m6aViewer: software for the detection, analysis, and visualization of N⁶-methyladenosine peaks from m⁶A-seq/ME-RIP sequencing data. RNA. 2017; 23:1493–501. https://doi.org/10.1261/rna.058206.116 [PubMed]
• 282. Xiang S, Liu K, Yan Z, Zhang Y, Sun Z. RNAMethPre: A Web Server for the Prediction and Query of mRNA m6A Sites. PLoS One. 2016; 11:e0162707. https://doi.org/10.1371/journal.pone.0162707 [PubMed]
• 283. Chen K, Wei Z, Zhang Q, Wu X, Rong R, Lu Z, Su J, de Magalhães JP, Rigden DJ, Meng J. WHISTLE: a high-accuracy map of the human N6-methyladenosine (m6A) epitranscriptome predicted using a machine learning approach. Nucleic Acids Res. 2019; 47:e41. https://doi.org/10.1093/nar/gkz074 [PubMed]
• 284. Xiang S, Yan Z, Liu K, Zhang Y, Sun Z. AthMethPre: a web server for the prediction and query of mRNA m⁶A sites in Arabidopsis thaliana. Mol Biosyst. 2016; 12:3333–7. https://doi.org/10.1039/c6mb00536e [PubMed]
• 285. Wang X, Yan R. RFAthM6A: a new tool for predicting m⁶A sites in Arabidopsis thaliana. Plant Mol Biol. 2018; 96:327–37. https://doi.org/10.1007/s11103-018-0698-9 [PubMed]
• 286. Wang M, Xie J, Xu S. M6A-BiNP: predicting N⁶-methyladenosine sites based on bidirectional position-specific propensities of polynucleotides and pointwise joint mutual information. RNA Biol. 2021; 18:2498–512. https://doi.org/10.1080/15476286.2021.1930729 [PubMed]
• 287. Qiang X, Chen H, Ye X, Su R, Wei L. M6AMRFS: Robust Prediction of N6-Methyladenosine Sites With Sequence-Based Features in Multiple Species. Front Genet. 2018; 9:495. https://doi.org/10.3389/fgene.2018.00495 [PubMed]
• 288. Zhang L, Qin X, Liu M, Xu Z, Liu G. DNN-m6A: A Cross-Species Method for Identifying RNA N6-Methyladenosine Sites Based on Deep Neural Network with Multi-Information Fusion. Genes (Basel). 2021; 12:354. https://doi.org/10.3390/genes12030354 [PubMed]
• 289. Liang Z, Zhang L, Chen H, Huang D, Song B. m6A-Maize: Weakly supervised prediction of m⁶A-carrying transcripts and m⁶A-affecting mutations in maize (Zea mays). Methods. 2022; 203:226–32. https://doi.org/10.1016/j.ymeth.2021.11.010 [PubMed]
• 290. Abbas Z, Tayara H, Zou Q, Chong KT. TS-m6A-DL: Tissue-specific identification of N6-methyladenosine sites using a universal deep learning model. Comput Struct Biotechnol J. 2021; 19:4619–25. https://doi.org/10.1016/j.csbj.2021.08.014 [PubMed]
• 291. Dao FY, Lv H, Yang YH, Zulfiqar H, Gao H, Lin H. Computational identification of N6-methyladenosine sites in multiple tissues of mammals. Comput Struct Biotechnol J. 2020; 18:1084–91. https://doi.org/10.1016/j.csbj.2020.04.015 [PubMed]
• 292. Wang Y, Guo R, Huang L, Yang S, Hu X, He K. m6AGE: A Predictor for N6-Methyladenosine Sites Identification Utilizing Sequence Characteristics and Graph Embedding-Based Geometrical Information. Front Genet. 2021; 12:670852. https://doi.org/10.3389/fgene.2021.670852 [PubMed]
• 293. Zhang S, Wang J, Li X, Liang Y. M6A-GSMS: Computational identification of N⁶-methyladenosine sites with GBDT and stacking learning in multiple species. J Biomol Struct Dyn. 2022; 40:12380–91. https://doi.org/10.1080/07391102.2021.1970628 [PubMed]
• 294. Chen W, Feng P, Yang H, Ding H, Lin H, Chou KC. iRNA-3typeA: Identifying Three Types of Modification at RNA's Adenosine Sites. Mol Ther Nucleic Acids. 2018; 11:468–74. https://doi.org/10.1016/j.omtn.2018.03.012 [PubMed]
• 295. Chen W, Feng P, Ding H, Lin H, Chou KC. iRNA-Methyl: Identifying N(6)-methyladenosine sites using pseudo nucleotide composition. Anal Biochem. 2015; 490:26–33. https://doi.org/10.1016/j.ab.2015.08.021 [PubMed]
• 296. Huang Y, He N, Chen Y, Chen Z, Li L. BERMP: a cross-species classifier for predicting m⁶A sites by integrating a deep learning algorithm and a random forest approach. Int J Biol Sci. 2018; 14:1669–77. https://doi.org/10.7150/ijbs.27819 [PubMed]
• 297. Wei L, Chen H, Su R. M6APred-EL: A Sequence-Based Predictor for Identifying N6-methyladenosine Sites Using Ensemble Learning. Mol Ther Nucleic Acids. 2018; 12:635–44. https://doi.org/10.1016/j.omtn.2018.07.004 [PubMed]
• 298. Chen W, Feng P, Ding H, Lin H. Identifying N ⁶-methyladenosine sites in the Arabidopsis thaliana transcriptome. Mol Genet Genomics. 2016; 291:2225–9. https://doi.org/10.1007/s00438-016-1243-7 [PubMed]
• 299. Li GQ, Liu Z, Shen HB, Yu DJ. TargetM6A: Identifying N⁶-Methyladenosine Sites From RNA Sequences via Position-Specific Nucleotide Propensities and a Support Vector Machine. IEEE Trans Nanobioscience. 2016; 15:674–82. https://doi.org/10.1109/TNB.2016.2599115 [PubMed]
• 300. Liu Z, Xiao X, Yu DJ, Jia J, Qiu WR, Chou KC. pRNAm-PC: Predicting N(6)-methyladenosine sites in RNA sequences via physical-chemical properties. Anal Biochem. 2016; 497:60–7. https://doi.org/10.1016/j.ab.2015.12.017 [PubMed]
• 301. Zhang M, Sun JW, Liu Z, Ren MW, Shen HB, Yu DJ. Improving N(6)-methyladenosine site prediction with heuristic selection of nucleotide physical-chemical properties. Anal Biochem. 2016; 508:104–13. https://doi.org/10.1016/j.ab.2016.06.001 [PubMed]
• 302. Chen W, Xing P, Zou Q. Detecting N⁶-methyladenosine sites from RNA transcriptomes using ensemble Support Vector Machines. Sci Rep. 2017; 7:40242. https://doi.org/10.1038/srep40242 [PubMed]
• 303. Feng P, Ding H, Yang H, Chen W, Lin H, Chou KC. iRNA-PseColl: Identifying the Occurrence Sites of Different RNA Modifications by Incorporating Collective Effects of Nucleotides into PseKNC. Mol Ther Nucleic Acids. 2017; 7:155–63. https://doi.org/10.1016/j.omtn.2017.03.006 [PubMed]
• 304. Xing P, Su R, Guo F, Wei L. Identifying N⁶-methyladenosine sites using multi-interval nucleotide pair position specificity and support vector machine. Sci Rep. 2017; 7:46757. https://doi.org/10.1038/srep46757 [PubMed]
• 305. Akbar S, Hayat M. iMethyl-STTNC: Identification of N⁶-methyladenosine sites by extending the idea of SAAC into Chou's PseAAC to formulate RNA sequences. J Theor Biol. 2018; 455:205–11. https://doi.org/10.1016/j.jtbi.2018.07.018 [PubMed]
• 306. Zou Q, Xing P, Wei L, Liu B. Gene2vec: gene subsequence embedding for prediction of mammalian N⁶-methyladenosine sites from mRNA. RNA. 2019; 25:205–18. https://doi.org/10.1261/rna.069112.118 [PubMed]
• 307. Chen W, Ding H, Zhou X, Lin H, Chou KC. iRNA(m6A)-PseDNC: Identifying N⁶-methyladenosine sites using pseudo dinucleotide composition. Anal Biochem. 2018; 561–562:59–65. https://doi.org/10.1016/j.ab.2018.09.002 [PubMed]
• 308. Song B, Chen K, Tang Y, Wei Z, Su J, de Magalhães JP, Rigden DJ, Meng J. ConsRM: collection and large-scale prediction of the evolutionarily conserved RNA methylation sites, with implications for the functional epitranscriptome. Brief Bioinform. 2021; 22:bbab088. https://doi.org/10.1093/bib/bbab088 [PubMed]
• 309. Zhang SY, Zhang SW, Tang Y, Fan XN, Meng J. Funm6AViewer: a web server and R package for functional analysis of context-specific m6A RNA methylation. Bioinformatics. 2021; 37:4277–9. https://doi.org/10.1093/bioinformatics/btab362 [PubMed]
• 310. Pratanwanich PN, Yao F, Chen Y, Koh CWQ, Wan YK, Hendra C, Poon P, Goh YT, Yap PML, Chooi JY, Chng WJ, Ng SB, Thiery A, et al. Identification of differential RNA modifications from nanopore direct RNA sequencing with xPore. Nat Biotechnol. 2021; 39:1394–402. https://doi.org/10.1038/s41587-021-00949-w [PubMed]
• 311. Xiong Y, He X, Zhao D, Tian T, Hong L, Jiang T, Zeng J. Modeling multi-species RNA modification through multi-task curriculum learning. Nucleic Acids Res. 2021; 49:3719–34. https://doi.org/10.1093/nar/gkab124 [PubMed]
• 312. Leger A, Amaral PP, Pandolfini L, Capitanchik C, Capraro F, Miano V, Migliori V, Toolan-Kerr P, Sideri T, Enright AJ, Tzelepis K, van Werven FJ, Luscombe NM, et al. RNA modifications detection by comparative Nanopore direct RNA sequencing. Nat Commun. 2021; 12:7198. https://doi.org/10.1038/s41467-021-27393-3 [PubMed]
• 313. Su D, Chan CT, Gu C, Lim KS, Chionh YH, McBee ME, Russell BS, Babu IR, Begley TJ, Dedon PC. Quantitative analysis of ribonucleoside modifications in tRNA by HPLC-coupled mass spectrometry. Nat Protoc. 2014; 9:828–41. https://doi.org/10.1038/nprot.2014.047 [PubMed]
• 314. Yuen KC, Xu B, Krantz ID, Gerton JL. NIPBL Controls RNA Biogenesis to Prevent Activation of the Stress Kinase PKR. Cell Rep. 2016; 14:93–102. https://doi.org/10.1016/j.celrep.2015.12.012 [PubMed]