Recoding RNA editing of AZIN1 predisposes to hepatocellular carcinoma

RNA editing provides epigenetic diversity and is thought to be decreased in cancer. However, this report describes a phenomenon of increased RNA editing associated with malignancy in human liver tumors. The increased editing of AZIN1 is facilitated by the correlative increase in the editing enzyme ADAR1 and induces an amino acid change that leads to subcellular relocalization, increased stability and affinity for antizyme. This effect impairs antizyme's function and increases the stability of its target oncoproteins, providing protumorigenic functions. The hyperediting of AZIN1 is a protumorigenic event in liver cancer pathogenesis. A better understanding of human hepatocellular carcinoma (HCC) pathogenesis at the molecular level will facilitate the discovery of tumor-initiating events. Transcriptome sequencing revealed that adenosine-to-inosine (A→I) RNA editing of AZIN1 (encoding antizyme inhibitor 1) is increased in HCC specimens. A→I editing of AZIN1 transcripts, specifically regulated by ADAR1 (encoding adenosine deaminase acting on RNA-1), results in a serine-to-glycine substitution at residue 367 of AZIN1, located in β-strand 15 (β15) and predicted to cause a conformational change, induced a cytoplasmic-to-nuclear translocation and conferred gain-of-function phenotypes that were manifested by augmented tumor-initiating potential and more aggressive behavior. Compared with wild-type AZIN1 protein, the edited form has a stronger affinity to antizyme, and the resultant higher AZIN1 protein stability promotes cell proliferation through the neutralization of antizyme-mediated degradation of ornithine decarboxylase (ODC) and cyclin D1 (CCND1). Collectively, A→I RNA editing of AZIN1 may be a potential driver in the pathogenesis of human cancers, particularly HCC.