METTL1/WDR4-mediated m7G tRNA modifications and m7G codon usage promote mRNA translation and lung cancer progression.

Abstract

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.

• Authors: Jieyi Ma, Hui Han, Ying Huang, Chunlong Yang, Siyi Zheng, Tiancai Cai, Jiong Bi, Xiaohui Huang, Ruiming Liu, Libin Huang, Yifeng Luo, Wen Li, Shuibin Lin
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 29 Issue 12 Pg. 3422-3435 (12 01 2021) ISSN: 1525-0024 [Electronic] United States
• PMID: 34371184 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Chemical References

• WDR4 protein, human
• RNA, Transfer
• METTL1 protein, human
• Methyltransferases
• GTP-Binding Proteins

Topics

• Codon Usage
• GTP-Binding Proteins (genetics, metabolism)
• Humans
• Lung Neoplasms (genetics)
• Methyltransferases (genetics, metabolism)
• Protein Biosynthesis
• RNA, Transfer (genetics)