Mis-regulated epigenetic modifications in RNAs are associated with human cancers. The transfer RNAs (tRNAs) are the most heavily modified RNA species in cells; however, little is known about the functions of tRNA modifications in cancers. In this study, we uncovered that the expression levels of tRNA N⁷-methylguanosine (m⁷G) methyltransferase complex components methyltransferase-like 1 (METTL1) and WD repeat domain 4 (WDR4) are significantly elevated in human lung cancer samples and negatively associated with patient prognosis. Impaired m⁷G tRNA modification upon METTL1/WDR4 depletion resulted in decreased cell proliferation, colony formation, cell invasion, and impaired tumorigenic capacities of lung cancer cells in vitro and in vivo. Moreover, gain-of-function and mutagenesis experiments revealed that METTL1 promoted lung cancer growth and invasion through regulation of m⁷G tRNA modifications. Profiling of tRNA methylation and mRNA translation revealed that highly translated mRNAs have higher frequencies of m⁷G tRNA-decoded codons, and knockdown of METTL1 resulted in decreased translation of mRNAs with higher frequencies of m⁷G tRNA codons, suggesting that tRNA modifications and codon usage play an essential function in mRNA translation regulation. Our data uncovered novel insights on mRNA translation regulation through tRNA modifications and the corresponding mRNA codon compositions in lung cancer, providing a new molecular basis underlying lung cancer progression.

RNA 中错误调节的表观遗传修饰与人类癌症有关。转移 RNA (tRNA) 是细胞中修饰最重的 RNA 种类；然而，人们对 tRNA 修饰在癌症中的功能知之甚少。在这项研究中，我们发现 tRNA N ⁷ -甲基鸟苷(m ⁷ G) 甲基转移酶复合物组分甲基转移酶样 1 (METTL1) 和 WD 重复结构域 4 (WDR4) 的表达水平在人类肺癌样本中显着升高并且呈负相关与患者预后。METTL1/WDR4 耗尽后受损的 m ⁷ G tRNA 修饰导致细胞增殖减少、集落形成、细胞侵袭以及肺癌细胞在体外和体外的致瘤能力受损体内。^{此外，功能获得和诱变实验表明，METTL1 通过调节 m 7} G tRNA 修饰促进肺癌的生长和侵袭。tRNA 甲基化和 mRNA 翻译的分析表明，高度翻译的 mRNA 具有更高频率的 m ⁷ G tRNA 解码密码子，并且 METTL1 的敲低导致具有更高频率的 m ⁷ G tRNA 密码子的 mRNA 翻译减少，表明 tRNA 修饰和密码子用法在 mRNA 翻译调节中起着重要作用。我们的数据通过 tRNA 修饰和肺癌中相应的 mRNA 密码子组成揭示了 mRNA 翻译调控的新见解，为肺癌进展提供了新的分子基础。