METTL3/YTHDF2 m6A axis promotes tumorigenesis by degrading SETD7 and KLF4 mRNAs in bladder cancer
METTL3/YTHDF2 m6A axis promotes tumorigenesis by degrading SETD7 and KLF4 mRNAs in bladder cancer
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METTL3/YTHDF2 m(6)A 轴通过降解膀胱癌中的 SETD7 和 KLF4 mRNA 促进肿瘤发生
DOI：
10.1111/jcmm.15063
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发表时间：
2020-03-03
影响因子：
5.3
通讯作者：
Xie, Liping
中科院分区：
文献类型：
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作者：
Xie, Haiyun;Li, Jiangfeng;Xie, Liping
N6-甲基腺苷（m（6）A）修饰是真核生物信使RNA（mRNA）最普遍的修饰，参与各种肿瘤的进展。然而，m（6）A在膀胱癌（BCa）中的具体作用仍然知之甚少。在本研究中，我们证明了m（6）A轴的促肿瘤功能和特定的调节机制，包括核心的'作家'蛋白质胃L3和主要的阅读器蛋白质YTHDF 2。在体外和体内，胃L3的消耗损害癌症增殖和癌症转移。通过转录组测序、m（6）A甲基化RNA免疫沉淀（MeRIP）和RIP，我们确定了胃L3/YTHDF 2 m（6）A轴直接降解肿瘤抑制因子SET D 7和KLF 4的mRNA，从而促进BCa的进展。此外，SETD 7和KLF 4的过表达揭示了与m（6）A轴缺失诱导的表型一致的表型。因此，我们对胃L3/YTHDF 2/SETD 7/KLF 4 m（6）A轴的发现提供了对致癌的潜在机制的深入了解，并突出了BCa的潜在治疗靶点。
N6-Methyladenosine (m(6)A) modification, the most prevalent modification of eukaryotic messenger RNA (mRNA), is involved in the progression of various tumours. However, the specific role of m(6)A in bladder cancer (BCa) is still poorly understood. In this study, we demonstrated the tumour-promoting function and specific regulatory mechanism of m(6)A axis, consisting of the core 'writer' protein METTL3 and the major reader protein YTHDF2. Depletion of METTL3 impaired cancer proliferation and cancer metastasis in vitro and in vivo. Through transcriptome sequencing, m(6)A methylated RNA immunoprecipitation (MeRIP) and RIP, we determined that the METTL3/YTHDF2 m(6)A axis directly degraded the mRNAs of the tumour suppressors SETD7 and KLF4, contributing to the progression of BCa. In addition, overexpression of SETD7 and KLF4 revealed a phenotype consistent with that induced by depletion of the m(6)A axis. Thus, our findings on the METTL3/YTHDF2/SETD7/KLF4 m(6)A axis provide the insight into the underlying mechanism of carcinogenesis and highlight potential therapeutic targets for BCa.