METTL5-mediated 18S rRNA m⁶A modification promotes oncogenic mRNA translation and intrahepatic

Intrahepatic cholangiocarcinoma (ICC) is a deadly cancer with rapid tumor progression. While hyperactive mRNA translation caused by mis-regulated mRNA or tRNA modifications promotes ICC development, the role of rRNA modifications remains elusive. Here, we found that 18S rRNA m(6)A modification and its methyltransferase METTL5 were aberrantly upregulated in ICC and associated with poorer survival (log rank test, p < 0.05). We further revealed the critical role of METTL5-mediated 18S rRNA m(6)A modification in regulation of ICC cell growth and metastasis using loss- and gain-of function assays in vitro and in vivo. The oncogenic function of METTL5 is corroborated using liver-specific knockout and overexpression ICC mouse models. Mechanistically, METTL5 depletion impairs 18S rRNA m(6)A modification that hampers ribosome synthesis and inhibits translation of G-quadruplex-containing mRNAs that are enriched in the transforming growth factor (TGF)-beta pathway. Our study uncovers the important role of METTL5-mediated 18S rRNA m(6)A modification in ICC and unravels the mechanism of rRNA m(6)A modification-mediated oncogenic mRNA translation control.