GSE174492
METTL1 promotes hepatocarcinogenesis via m7G tRNA modification dependent translation control
N7-methylguanosine (m7G) modification is one of the most prevalent tRNA modifications in human. The precise function and molecular mechanism of m7G tRNA modification in regulation of cancer remain poorly understood. Here we showed that m7G tRNA modification, METTL1 and WDR4 are elevated in hepatocellular carcinoma (HCC) tissues and associated with HCC patient prognosis. Functionally, silencing METTL1 or WDR4 inhibits HCC cell proliferation, migration and invasion, while forced expression of wild type METTL1 but not its catalytic dead mutant promotes HCC progression. Knockdown of METTL1 reduces m7G tRNA modification and decreases m7G modified tRNA expression. Mechanistically, METTL1 depletion selectively decreases the mRNA translation of a subset of oncogenic genes, especially cell cycle and EGFR pathway genes, in m7G-related codon dependent manner. Moreover, in vivo studies using Mettl1 knock-in and knockout mice reveal a critical function of Mettl1 mediated m7G tRNA modifications in promoting hepatocarcinogenesis in the hydrodynamics transfection HCC model. Our work uncovers the critical functions of tRNA m7G modification in regulating cancer mRNA translation and promoting hepatocarcinogenesis, thus provides new insights into role of the mis-regulated tRNA modifications in cancers. Overall design: TRAC-Seq were developed to identify the tRNA m7G methylome in hepatocellular carcinoma cell line and c57 mouse liver tumor tissue. Polyribosome associated mRNA sequencing was used to study the differential translated genes in the Mettl1 knockdown and control cells.