Dynamic m6A mRNA methylation reveals the role of METTL3-m6A-CDCP1 signaling axis in chemical carcinogenesis
Dynamic m6A mRNA methylation reveals the role of METTL3-m6A-CDCP1 signaling axis in chemical carcinogenesis
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动态m(6)A mRNA甲基化揭示METTL3-m(6)A-CDCP1信号轴在化学致癌作用中的作用
DOI：
10.1038/s41388-019-0755-0
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发表时间：
2019-06-13
期刊：
影响因子：
8
通讯作者：
Ji, Weidong
中科院分区：
文献类型：
--
作者：
Yang, Fan;Jin, Huan;Ji, Weidong
N6 - 甲基腺苷（m(6)A）是哺乳动物mRNA中最丰富的内部修饰。尽管它在各种生理事件中具有重要功能，但m(6)A在化学致癌作用中的角色在很大程度上仍然未知。在此，我们分析了化学致癌物诱导细胞转化过程中动态的m(6)A mRNA修饰，并确定了一组与细胞转化相关且协同调节的m(6)A位点。值得注意的是，在恶性转化细胞中发现癌基因CDCP1的3' - 非翻译区（3' - UTR）mRNA中的m(6)A增加。从机制上讲，m(6)A甲基转移酶METTL3和去甲基化酶ALKBH5介导CDCP1 mRNA 3' - UTR中的m(6)A修饰。METTL3和m(6)A阅读蛋白YTHDF1优先识别CDCP1 3' - UTR上的m(6)A残基并促进CDCP1的翻译。我们进一步表明，METTL3和CDCP1在膀胱癌患者样本中上调，并且METTL3和CDCP1的表达与膀胱癌的进展状态相关。抑制METTL3 - m(6)A - CDCP1轴导致化学转化细胞和膀胱癌细胞的生长和进展降低。最重要的是，METTL3 - m(6)A - CDCP1轴在体外和体内与化学致癌物在促进尿路上皮细胞恶性转化和膀胱癌发生方面具有协同作用。总之，我们的结果确定了化学诱导的恶性转化中的动态m(6)A修饰，并提供了对METTL3 - m(6)A - CDCP1轴在化学致癌作用中关键作用的深入了解。
N6-methyladenosine (m(6)A) is the most abundant internal modification in mammalian mRNAs. Despite its functional importance in various physiological events, the role of m(6)A in chemical carcinogenesis remains largely unknown. Here we profiled the dynamic m(6)A mRNA modification during cellular transformation induced by chemical carcinogens and identified a subset of cell transformation-related, concordantly modulated m(6)A sites. Notably, the increased m(6)A in 3'-UTR mRNA of oncogene CDCP1 was found in malignant transformed cells. Mechanistically, the m(6)A methyltransferase METTL3 and demethylases ALKBH5 mediate the m(6)A modification in 3'-UTR of CDCP1 mRNA. METTL3 and m(6)A reader YTHDF1 preferentially recognize m(6)A residues on CPCP1 3'-UTR and promote CDCP1 translation. We further showed that METTL3 and CDCP1 are upregulated in the bladder cancer patient samples and the expression of METTL3 and CDCP1 is correlated with the progression status of the bladder cancers. Inhibition of the METTL3-m(6)A-CDCP1 axis resulted in decreased growth and progression of chemical-transformed cells and bladder cancer cells. Most importantly, METTL3-m(6)A-CDCP1 axis has synergistic effect with chemical carcinogens in promoting malignant transformation of uroepithelial cells and bladder cancer tumorigenesis in vitro and in vivo. Taken together, our results identify dynamic m(6)A modification in chemical-induced malignant transformation and provide insight into critical roles of the METTL3-m(6)A-CDCP1 axis in chemical carcinogenesis.