FTO promotes proliferation and migration of bladder cancer via enhancing stability of STAT3 mRNA in an m6A-dependent manner

N6-Methyladenosine (m6A) plays a key role in the occurrence and development of various cancers. Fat mass and obesity‐associated protein (FTO) was is involved in multiple cancers owing to its demethylase activity, and the molecular mechanism underlying FTO-promoted bladder cancer proliferation and migration via the regulation of RNA stability requires further investigation. In the present study, FTO was upregulated in bladder cancer and related to poor prognosis. Gain- and loss-of-function experiments showed that the upregulation of FTO promoted bladder cancer proliferation and migration. Mechanistic studies showed that FTO enhanced the stability of signal transducer and activator of transcription 3 (STAT3) mRNA in an m6A-dependent manner, thereby increasing STAT3 expression, which subsequently promoted P-STAT3 expression and activated STAT3 signalling pathway. Overall, this study revealed that the critical role of FTO in the progression of bladder cancer and could provide a novel avenue to regulate oncogene STAT3.

N6-甲基腺嘌呤（N6-Methyladenosine，m6A）在多种癌症的发生与发展中发挥关键作用。脂肪量与肥胖相关蛋白（Fat mass and obesity-associated protein，FTO）凭借其去甲基化酶活性参与多种癌症的发生发展，而FTO通过调控RNA稳定性促进膀胱癌增殖与迁移的潜在分子机制仍有待进一步阐明。本研究中，FTO在膀胱癌组织中呈高表达状态，且与不良预后显著相关。功能获得与功能缺失实验结果显示，FTO过表达可促进膀胱癌的增殖与迁移能力。机制研究表明，FTO以m6A依赖的方式增强信号转导与转录激活因子3（signal transducer and activator of transcription 3，STAT3）mRNA的稳定性，进而上调STAT3的表达水平，随后促进磷酸化STAT3（P-STAT3）的表达并激活STAT3信号通路。综上，本研究揭示了FTO在膀胱癌进展中的关键作用，可为靶向调控癌基因STAT3提供全新的研究思路与干预策略。