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

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

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

https://doi.org/10.18632/aging.202359

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.

Abstract

N6-methyladenosine refers to a methylation of adenosine base at the 6^th 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.