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

Aging (Albany NY). 2021 Jan 10;13(3):3909-3925. doi: 10.18632/aging.202359. Epub 2021 Jan 10.

Abstract

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.

Keywords: FTO; N6-methyladenosine; bladder cancer; m6A; methylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives
  • Adenosine / metabolism
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO / genetics*
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO / metabolism
  • Animals
  • Carcinogenesis / genetics*
  • Carcinoma, Transitional Cell / genetics*
  • Carcinoma, Transitional Cell / metabolism
  • Carcinoma, Transitional Cell / pathology
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation / genetics
  • Disease Progression
  • Gene Knock-In Techniques
  • Gene Knockdown Techniques
  • Humans
  • Methylation
  • Mice
  • Neoplasm Staging
  • Neoplasm Transplantation
  • Pyrroline Carboxylate Reductases / genetics*
  • Pyrroline Carboxylate Reductases / metabolism
  • RNA Processing, Post-Transcriptional
  • RNA Stability / genetics
  • RNA, Messenger / metabolism
  • Ubiquitin Thiolesterase / genetics*
  • Ubiquitin Thiolesterase / metabolism
  • Urinary Bladder Neoplasms / genetics*
  • Urinary Bladder Neoplasms / metabolism
  • Urinary Bladder Neoplasms / pathology
  • delta-1-Pyrroline-5-Carboxylate Reductase

Substances

  • RNA, Messenger
  • N-methyladenosine
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO
  • FTO protein, human
  • Pyrroline Carboxylate Reductases
  • USP18 protein, human
  • Ubiquitin Thiolesterase
  • Adenosine