METTL3介导的m6A修饰增强BIRC6蛋白翻译，促进肝脏肿瘤发生

Abstract

N 6 -methyladenosine (m 6 A) is the most prevalent internal modification of mRNA and is frequently dysregulated in cancer. However, the roles of m 6 A and its modifiers, such as the methyltransferase METTL3, remain controversial in primary tumors. We report that METTL3 is upregulated in the highly proliferative human S2 and mouse M2 subtypes of hepatocellular carcinoma (HCC). Integrated analyses of the RNA methylome, transcriptome and proteome identify Birc6 as a direct downstream target of Mettl3. Using CRISPR/dCas13b-mediated site-specific methylation, we demonstrate that m 6 A deposition at three conserved sites enhances Birc6 translation, thereby promoting degradation of caspase-7 and caspase-9 and suppressing apoptosis. Multiplexed in situ genome editing in mouse hepatocytes shows that Mettl3 promotes hepatocarcinogenesis in a cell-autonomous manner through Birc6 . Together, our findings establish a functional link between METTL3-mediated m 6 A modification and BIRC6-mediated apoptosis inhibition in liver tumorigenesis, suggesting BIRC6 as a potential therapeutic target in HCC.