N7-Methylguanosine tRNA modification enhances oncogenic mRNA translation and promotes intrahepatic cholangiocarcinoma progression
N7-Methylguanosine tRNA modification enhances oncogenic mRNA translation and promotes intrahepatic cholangiocarcinoma progression
复制标题
DOI：
10.1016/j.molcel.2021.07.003
复制
发表时间：
2021-08-19
期刊：
影响因子：
16
通讯作者：
Kuang, Ming
中科院分区：
文献类型：
--
作者：
Dai, Zihao;Liu, Haining;Kuang, Ming
癌细胞选择性地促进特定致癌转录物的翻译，以促进癌症的存活和进展，但其潜在机制尚不清楚。在这里，我们发现 N-7-甲基鸟苷 (m(7)G) tRNA 修饰及其甲基转移酶复合体成分 METTL1 和 WDR4 在肝内胆管癌 (ICC) 中显着上调，并与不良预后相关。我们通过体外和体内功能丧失和获得功能分析进一步揭示了 METTL/WDR4 在促进 ICC 细胞存活和进展中的关键作用。从机制上讲，m(7)G tRNA 修饰在 m(7)G-tRNA 解码的密码子频率依赖性机制中选择性调节致癌转录物的翻译，包括细胞周期和表皮生长因子受体 (EGFR) 途径基因。此外，利用过表达和基因敲除小鼠模型，我们证明了 Mettl1 介导的 m(7)G tRNA 修饰在促进体内 ICC 肿瘤发生和进展中的关键致癌功能。我们的研究揭示了 METTL1 介导的 m(7)G tRNA 修饰在调节致癌 mRNA 翻译和癌症进展中的重要生理功能和机制。
Cancer cells selectively promote translation of specific oncogenic transcripts to facilitate cancer survival and progression, but the underlying mechanisms are poorly understood. Here, we find that N-7-methylguanosine (m(7)G) tRNA modification and its methyltransferase complex components, METTL1 and WDR4, are significantly upregulated in intrahepatic cholangiocarcinoma (ICC) and associated with poor prognosis. We further reveal the critical role of METTL/WDR4 in promoting ICC cell survival and progression using loss- and gain-of-function assays in vitro and in vivo. Mechanistically, m(7)G tRNA modification selectively regulates the translation of oncogenic transcripts, including cell-cycle and epidermal growth factor receptor (EGFR) pathway genes, in m(7)G-tRNA-decoded codon-frequency-dependent mechanisms. Moreover, using overexpression and knockout mouse models, we demonstrate the crucial oncogenic function of Mettl1-mediated m(7)G tRNA modification in promoting ICC tumorigenesis and progression in vivo. Our study uncovers the important physiological function and mechanism of METTL1-mediated m(7)G tRNA modification in the regulation of oncogenic mRNA translation and cancer progression.