METTL5-mediated 18S RRNA MA Modification Promotes Oncogenic MRNA Translation and Intrahepatic Cholangiocarcinoma Progression

Overview

Journal Mol Ther

Publisher Cell Press

Specialties Molecular Biology
Pharmacology

Date 2023 Sep 22

PMID 37735874

Authors

Zihao Dai

Wanjie Zhu

Yingdong Hou

Xinyue Zhang

Xuxin Ren

Kai Lei

Junbin Liao

Haining Liu

Zhihang Chen

Sui Peng

Shaoqiang Li

Shuibin Lin

Ming Kuang

Affiliations

Soon will be listed here.

Abstract

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 mA 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 mA 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 mA modification that hampers ribosome synthesis and inhibits translation of G-quadruplex-containing mRNAs that are enriched in the transforming growth factor (TGF)-β pathway. Our study uncovers the important role of METTL5-mediated 18S rRNA mA modification in ICC and unravels the mechanism of rRNA mA modification-mediated oncogenic mRNA translation control.

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