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
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine / analogs & derivatives
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Adenosine / metabolism
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Alpha-Ketoglutarate-Dependent Dioxygenase FTO / genetics*
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Alpha-Ketoglutarate-Dependent Dioxygenase FTO / metabolism
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Animals
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Carcinogenesis / genetics*
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Carcinoma, Transitional Cell / genetics*
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Carcinoma, Transitional Cell / metabolism
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Carcinoma, Transitional Cell / pathology
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Cell Line, Tumor
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Cell Movement / genetics
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Cell Proliferation / genetics
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Disease Progression
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Gene Knock-In Techniques
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Gene Knockdown Techniques
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Humans
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Methylation
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Mice
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Neoplasm Staging
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Neoplasm Transplantation
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Pyrroline Carboxylate Reductases / genetics*
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Pyrroline Carboxylate Reductases / metabolism
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RNA Processing, Post-Transcriptional
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RNA Stability / genetics
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RNA, Messenger / metabolism
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Ubiquitin Thiolesterase / genetics*
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Ubiquitin Thiolesterase / metabolism
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Urinary Bladder Neoplasms / genetics*
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Urinary Bladder Neoplasms / metabolism
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Urinary Bladder Neoplasms / pathology
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delta-1-Pyrroline-5-Carboxylate Reductase
Substances
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RNA, Messenger
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N-methyladenosine
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Alpha-Ketoglutarate-Dependent Dioxygenase FTO
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FTO protein, human
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Pyrroline Carboxylate Reductases
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USP18 protein, human
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Ubiquitin Thiolesterase
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Adenosine