Research Paper Volume 13, Issue 3 pp 3909—3925

Dysregulation of USP18/FTO/PYCR1 signaling network promotes bladder cancer development and progression

Wei Song1, , Ke Yang1, , Jianjun Luo1, , Zhiyong Gao1, , Yunliang Gao2, ,

  • 1 Department of Urology, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410005, Hunan Province, China
  • 2 Department of Urology, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China

Received: July 11, 2020       Accepted: November 3, 2020       Published: January 10, 2021
How to Cite

Copyright: © 2021 Song 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.


N6-methyladenosine refers to a methylation of adenosine base at the 6th nitrogen position, which is the dominant methylation modification in both message and non-coding RNAs. Dysregulation of RNA m6A methylation causes tumorigenesis in humans. The key N6-methyladenosine demethylase fat-mass and obesity-associated protein (FTO) is negatively correlated with the overall survival of bladder cancer patients, but the underlying mechanism remains poorly understood. In this study, we demonstrated that the post-translational deubiquitination by USP18 up-regulates the protein but not mRNA of FTO in bladder cancer tissues and cells. As a result, FTO decreased N6-methyladenosine methylation level in PYCR1 through its demethylase enzymatic activity and stabilized PYCR1 transcript to promote bladder cancer initiation and progression. Our work shows the importance of N6-methyladenosine RNA modification in bladder cancer development, and highlights UPS18/FTO/PYCR1 signaling network as potential therapeutic targets of bladder cancer.


ALKBH5: ALKB homolog 5; BLCA: Bladder cancer; FTO: Fat-mass and obesity-associated; GEPIA: Gene Expression Profiling Interactive Analysis; hnRNPs: heterogeneous nuclear ribonucleoproteins; m6A: N6-methyladenosine; m7G: 7-methylguanosine; METTL3: methyltransferase-like 3; MTC: methyltransferase complex; PYCR1: pyrroline-5-carboxylate reductase 1; qPCR: quantitative PCR; RNA: mRNA; SNPs: single nucleotide polymorphisms; USP18: ubiquitin Specific Peptidase 18; WTAP: Wilm’s tumor 1-associated protein; YTH: YT521-B homology.