N7-Methylguanosine tRNA modification enhances oncogenic mRNA translation and promotes intrahepatic cholangiocarcinoma progression

• Published in: Molecular cell Vol. 81; no. 16; pp. 3339 - 3355.e8
• Main Authors: Dai, Zihao, Liu, Haining, Liao, Junbin, Huang, Cheng, Ren, Xiaoxue, Zhu, Wanjie, Zhu, Shenghua, Peng, Baogang, Li, Shaoqiang, Lai, Jiaming, Liang, Lijian, Xu, Lixia, Peng, Sui, Lin, Shuibin, Kuang, Ming
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 19.08.2021
• Subjects: animal disease models; biliary tract diseases; cell cycle; cell viability; epidermal growth factor receptors; G-proteins; gain-of-function mutation; gene overexpression; guanosine; knockout mutants; liver neoplasms; messenger RNA; methyltransferases; mice; neoplasm cells; neoplasm progression; oncogenes; transfer RNA; translation (genetics)
• ISSN: 1097-2765; 1097-4164; 1097-4164
• DOI: 10.1016/j.molcel.2021.07.003

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 N7-methylguanosine (m7G) 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 METTL1/WDR4 in promoting ICC cell survival and progression using loss- and gain-of-function assays in vitro and in vivo. Mechanistically, m7G tRNA modification selectively regulates the translation of oncogenic transcripts, including cell-cycle and epidermal growth factor receptor (EGFR) pathway genes, in m7G-tRNA-decoded codon-frequency-dependent mechanisms. Moreover, using overexpression and knockout mouse models, we demonstrate the crucial oncogenic function of Mettl1-mediated m7G tRNA modification in promoting ICC tumorigenesis and progression in vivo. Our study uncovers the important physiological function and mechanism of METTL1-mediated m7G tRNA modification in the regulation of oncogenic mRNA translation and cancer progression. [Display omitted] •METTL1-mediated m7G tRNA modification promotes ICC cancer progression•METTL1-mediated m7G tRNA modification regulates tRNA expression and mRNA translation•m7G tRNA selectively modulates translation in a codon-dependent manner•Oncogenic function of m7G tRNA modification is verified in multiple ICC mouse models Dai et al. show that METTL1-mediated m7G tRNA modification selectively regulates the translation of certain oncogenic transcripts and promotes intrahepatic cholangiocarcinoma progression in vitro and in vivo. The selective translation mechanism is regulated at the tRNA-mRNA codon recognition step in a codon-frequency-dependent manner.