Affiliations 1 Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, China. 2 Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, China. 3 Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, China. 4 Shandong University Cancer Center, Jinan, Shandong Province, China.
Background: Hepatocellular carcinoma ranks fourth among the malignancies leading to cancer-related deaths all around the world. It is increasingly evident that long non-coding RNAs are a key mode of hepatocarcinogenesis. As the most prevalent mRNA modification form, N -methyladenosine 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 A-methylated lncRNAs in HCC. Methods: The m...更多
Background: Hepatocellular carcinoma ranks fourth among the malignancies leading to cancer-related deaths all around the world. It is increasingly evident that long non-coding RNAs are a key mode of hepatocarcinogenesis. As the most prevalent mRNA modification form, N -methyladenosine 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 A-methylated lncRNAs in HCC. Methods: The m 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 A-seq data of HCC cells, we identified 22 candidate lncRNAs with evidently dysregulated m A levels. Among these lncRNAs, we found that ARHGAP5-AS1 is the lncRNA with the highest levels of m A modification and significantly increased expression in HCC specimens. METTL14 acts as the m A writer of ARHGAP5-AS1 and IGF2BP2 stabilises the lncRNA as its m 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 A-modified lncRNAs controlling CSDE1-mediated oncogenic RNA regulons and highlights lncRNAs as potential targets for future therapeutics against HCC.收起
