Journal
AGING-US
Volume 13, Issue 3, Pages 3909-3925Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/aging.202359
Keywords
N6-methyladenosine; m6A; methylation; FTO; bladder cancer
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Funding
- Hunan Provincial Health Commission [20200053]
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N6-methyladenosine is a crucial RNA modification that plays a key role in bladder cancer development, and the mechanism involves the regulation of PYCR1 expression by fat-mass and obesity-associated protein (FTO) through its demethylase activity. Our study highlights the UPS18/FTO/PYCR1 signaling network as potential therapeutic targets for bladder cancer.
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.
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