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

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RNA editing introduces nucleotide changes in RNA sequences. Recent studies have reported 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).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 tumorigenesis between wild-type and edited COPA (COPAWTvs COPAI164V) and the exact mechanisms were also studied in cell models and mice.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, COPAWT switches from a tumor-promoting gene to a tumor suppressor that has a dominant-negative effect. Moreover, COPAI164V may undergo protein conformational change and therefore become less stable than COPAWT. Mechanistically, COPAI164V may deactivate the PI3K/Akt/mTOR pathway through downregulation of caveolin-1 (CAV1).We uncover an RNA editing-associated mechanism of hepatocarcinogenesis by which downregulation of ADAR2 caused the loss of tumor suppressive COPAI164V and concurrent accumulation of tumor-promoting COPAWT in tumors; and a rapid degradation of COPAI164V protein and hyper-activation of PI3K/Akt/mTOR pathway further promote tumorigenesis.

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