original data of METTL5-mediated 18S rRNA m6A modification promotes oncogenic mRNA translation and intrahepatic cholangiocarcinoma progression

Published: 6 April 2023| Version 1 | DOI: 10.17632/xfs5tpbx6j.1
zihao Dai,
wanjie zhu,
yingdong hou,
zhang xinyue,
xuxin ren,
kai lei,
Junbin Liao,
Haining Liu,
zhihang chen,
Sui Peng,
shaoqiang li,
Shuibin Lin,
Ming Kuang


Intrahepatic cholangiocarcinoma (ICC) is a highly lethal malignancy characterized by rapid tumor progression. Hyperactive mRNA translation driven by mis-regulated RNA modifications has emerged as an essential oncogenic mechanism in ICC. While mRNA and tRNA modifications have been intensively studied, the function and mechanism of ribosomal RNA (rRNA) modifications, however, remain poorly understood in cancer biology. 18S rRNA m6A is one of the two m6A modification in human rRNA catalyzed by methyltransferase METTL5. Despite its emerging functional importance in regulation of stem cell fate and growth, the role of 18S rRNA m6A modification in cancers remains largely unclear. Here we found that 18S rRNA m6A modification and METTL5 are aberrantly upregulated in ICC and associate with poor clinical survival. We further revealed the critical role of METTL5-mediated 18S rRNA m6A modification in regulation of ICC cell growth and metastasis using loss- and gain-of function assays in vitro and in vivo. The crucial oncogenic function of METTL5 was further corroborated using liver-specific knockout and overexpression ICC mouse models. Mechanistically, METTL5 depletion impairs 18S rRNA m6A modification level that hampers ribosome synthesis, which preferentially results in the translation inhibition of G-quadruplexes-containing mRNAs that enriched in many oncogenic signals including TGF-beta pathway. There are two novel findings in this original research. First, we disclose the important physiological functions of METTL5-mediated 18S rRNA m6A modification in ICC, uncovering an important link between rRNA modifications and cancer development. Second, we find that METTL5-mediated 18S rRNA m6A modification preferentially modulate the translation of certain oncogenic transcripts containing G-quadruplexes and shorter 5’-UTR length due to the impaired ribosome synthesis. Excepting mRNA and tRNA modifications, our study reveals an additional layer of selective regulation of gene expression mediated by rRNA modification, providing new strategies targeting abnormal translation for effective ICC treatment from rRNA modification layer.



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