Research Paper Advance Articles

ESRP1 regulates alternative splicing of CARM1 to sensitize small cell lung cancer cells to chemotherapy by inhibiting TGF-β/Smad signaling

Meng Zheng1, *, , Yuchun Niu1, *, , Junguo Bu4, *, , Shumei Liang1, , Zhilin Zhang5, , Jianhua Liu2, , Linlang Guo1, , Zhihua Zhang2, , Qiongyao Wang3, ,

  • 1 Department of Pathology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
  • 2 Department of Respiratory Medicine, The First Affiliated Hospital of Hebei North University, Zhangjiakou, China
  • 3 Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
  • 4 Department of Radiotherapy, Zhujiang Hospital, Southern Medical University, Guangzhou, China
  • 5 Department of Radiotherapy, The First Affiliated Hospital of Hebei North University, Zhangjiakou, China
* Equal contribution

Received: April 17, 2020       Accepted: October 8, 2020       Published: January 20, 2021      

https://doi.org/10.18632/aging.202295
How to Cite

Copyright: © 2021 Zheng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Epithelial splicing regulatory protein 1 (ESRP1) is an RNA-binding protein that regulates alternative splicing of mRNA. ESRP1 plays an important role in chemoresistance of various cancers, including breast cancer, colon cancer and non-small cell lung cancer. However, the role of ESRP1 and its mechanism in small cell lung cancer (SCLC) chemoresistance remains unclear. In this study, we found that ESRP1 is significantly downregulated in SCLC chemo-resistant cells compared with chemo-sensitive cells. Moreover, the expression of ESRP1 was significantly lower in SCLC tissues than that in normal adjacent tissues and positively correlated with overall survival. Overexpression of ESRP1 increased SCLC chemosensitivity, and induced cell apoptosis and cell cycle arrest, whereas knockdown of ESRP1 induced the opposite effects. ESRP1 could inhibit the growth of SCLC in vivo. Through mRNA transcriptome sequencing, we found that ESRP1 regulates coactivator-associated arginine methyltransferase 1 (CARM1) to produce two different transcripts CARM1FL and CARM1ΔE15 by alternative splicing. ESRP1 affects the chemoresistance of SCLC by changing the content of different transcripts of CARM1. Furthermore, CARM1 regulates arginine methylation of Smad7, activates the TGF-β/Smad pathway and induces epithelial-to-mesenchymal transition (EMT), thereby promoting SCLC chemoresistance. Collectively, our study firstly demonstrates that ESRP1 inhibits the TGF-β/Smad signaling pathway by regulating alternative splicing of CARM1, thereby reversing chemoresistance of SCLC. The splicing factor ESRP1 may serve as a new drug resistance marker molecule and a potential therapeutic target in SCLC patients.

Abbreviations

ESRP1: Epithelial splicing regulatory protein 1; CARM1: Coactivator associated arginine methyltransferase 1; AS: Alternative splicing; PRMT: Protein arginine methyltransferase; SCLC: Small cell lung cancer; NSCLC: Non-small cell lung cancer; TGF-β: Transforming growth factor-β; EMT: Epithelial-mesenchymal transition; ADOX: Adenosine dialdehyde; GAPDH: Glyceraldehyde-3-phosphate dehydrogenase; PARP: Poly ADP-ribose polymerase; BAX: BCL2-Associated X; IC50: 50% inhibitory concentration; PCR: Polymerase Chain Reaction; qRT-PCR: Quantitative real time polymerase chain reaction; RIP: RNA immunoprecipitation; Co-IP: Co-immunoprecipitation; CCK8: Cell counting kit-8.