期刊
CLINICAL AND TRANSLATIONAL MEDICINE
卷 12, 期 11, 页码 -出版社
JOHN WILEY & SONS LTD
DOI: 10.1002/ctm2.1107
关键词
ARHGAP5-AS1; N-6-methyladenosine; lncRNA; CSDE1; hepatocellular carcinoma
资金
- National Natural Science Foundation of China [31871306, 82173070, 82103291]
- Natural Science Foundation of Shandong Province [ZR2021LZL004, ZR202102250889]
- Major Scientific and Technological Innovation Project of Shandong Province [2021ZDSYS04]
- Program of Science and Technology for the youth innovation team in universities of Shandong Province [2020KJL001]
This study identifies the biologic functions of m(6)A-modified lncRNA ARHGAP5-AS1 in HCC and reveals its promotion of hepatocarcinogenesis through controlling CSDE1-mediated oncogenic RNA regulons.
Background Hepatocellular carcinoma (HCC) ranks fourth among the malignancies leading to cancer-related deaths all around the world. It is increasingly evident that long non-coding RNAs (lncRNAs) are a key mode of hepatocarcinogenesis. As the most prevalent mRNA modification form, N-6-methyladenosine (m(6)A) regulates gene expression by impacting multiple aspects of mRNA metabolism. However, there are still no reports on genome-wide screening and functional annotation of m(6)A-methylated lncRNAs in HCC. Methods The m(6)A modification and biologic functions of ARHGAP5-AS1 in HCC were investigated through a series of biochemical assays. Clinical implications of ARHGAP5-AS1 were examined in tissues from HCC patients. Results After systematically analysing the m(6)A-seq data of HCC cells, we identified 22 candidate lncRNAs with evidently dysregulated m(6)A levels. Among these lncRNAs, we found that ARHGAP5-AS1 is the lncRNA with the highest levels of m(6)A modification and significantly increased expression in HCC specimens. METTL14 acts as the m(6)A writer of ARHGAP5-AS1 and IGF2BP2 stabilises the lncRNA as its m(6)A reader. ARHGAP5-AS1 remarkably promotes malignant behaviours of HCC cells ex vivo and in vivo. We identified oncoprotein CSDE1 working as the interacting protein of the lncRNA and TRIM28 as the E3 ligase of CSDE1 in HCC. Interestingly, ARHGAP5-AS1 could attenuate interactions between CSDE1 and TRIM28, which prevents the degradation of CSDE1 via the ubiquitin-proteasome pathway. Elevated levels of CSDE1 coordinate oncogenic RNA regulons, promote translation of VIM and RAC1 and activate the ERK pathway, which contributes to HCC prognosis. Conclusions Our study reveals a new paradigm in m(6)A-modified lncRNAs controlling CSDE1-mediated oncogenic RNA regulons and highlights lncRNAs as potential targets for future therapeutics against HCC.
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