RNA editing mediates the functional switch of COPA in a novel mechanism of hepatocarcinogenesis

作者：Yangyang Song, Ömer An, Xi Ren, Tim Hon Man Chan, Daryl Jin Tai Tay, Sze Jing Tang, Jian Han, HuiQi Hong, Vanessa Hui En Ng, Xinyu Ke, Haoqing Shen, Priyankaa Pitcheshwar, Jaymie Siqi Lin, Ka Wai Leong, Fernando Bellido Molías, Henry Yang, Dennis Kappei, Leilei Chen · 发表于：Journal of Hepatology · 年份：2020 · DOI：10.1016/j.jhep.2020.07.021 · 被引用次数：76 · 研究领域：RNA regulation and disease、Cancer-related molecular mechanisms research、RNA modifications and cancer

Background & Aims RNA editing introduces nucleotide changes in RNA sequences. Recent studies have reported that aberrant adenosine-to-inosine RNA editing is implicated in cancers. Until now, very few functionally important protein-recoding editing targets have been discovered. Here, we investigated the role of a recently discovered protein-recoding editing target COPA (coatomer subunit α) in hepatocellular carcinoma (HCC). Methods Clinical implication of COPA editing was studied in a cohort of 125 HCC patients. CRISPR/Cas9-mediated knockout of the editing site complementary sequence (ECS) was used to delete edited COPA transcripts endogenously. COPA editing-mediated change in its transcript or protein stability was investigated upon actinomycin D or cycloheximide treatment, respectively. Functional difference in tumourigenesis between wild-type and edited COPA ( COPA WT vs. COPA I164V ) and the exact mechanisms were also studied in cell models and mice. Results ADAR2 binds to double-stranded RNA formed between edited exon 6 and the ECS at intron 6 of COPA pre-mRNA, causing an isoleucine-to-valine substitution at residue 164. Reduced editing of COPA is implicated in the pathogenesis of HCC, and more importantly, it may be involved in many cancer types. Upon editing, COPA WT switches from a tumour-promoting gene to a tumour suppressor that has a dominant-negative effect. Moreover, COPA I164V may undergo protein conformational change and therefore become less stable than COPA WT...