Major finding: RNA editing of AZIN1 is increased in HCC and enhances tumor incidence and progression.
Mechanism: Edited AZIN1 promotes proliferation by blocking antizyme-mediated degradation of ODC and CCND1.
Impact: Adenosine-to-inosine recoding of AZIN1 confers a gain of function that drives tumorigenesis.
RNA editing is a regulatory mechanism in which nucleotides are altered posttranscriptionally and most frequently involves conversion of adenosine to inosine, which is recognized as a guanosine during translation. Chen and colleagues performed RNA sequencing analysis to identify molecular changes in hepatocellular carcinoma (HCC) samples that might contribute to disease progression, and they detected elevated adenosine-to-inosine RNA editing of antizyme inhibitor 1 (AZIN1) in HCC samples compared with adjacent normal tissues. The frequency of AZIN1 editing increased during HCC progression and was correlated with liver cirrhosis, tumor recurrence, and poor prognosis, suggesting that this recoding event may promote HCC pathogenesis. AZIN1 RNA modification was mediated by the p110 isoform of adenosine deaminase, RNA-specific (ADAR1), but not by other ADAR family members, and resulted in substitution of glycine for serine at residue 367 in the AZIN1 protein, which was predicted to induce a conformational switch. This amino acid change triggered cytoplasmic-to-nuclear translocation of AZIN1 in HCC samples and conferred a gain-of-function phenotype in tumor cell lines; expression of edited AZIN1 increased cell proliferation, anchorage-independent growth, and invasion and augmented tumor incidence in mice, supporting a protumorigenic function for this edited protein. Mechanistically, edited AZIN1 exhibited increased binding affinity for antizyme, a tumor suppressor that inhibits proliferation, and enhanced protein stability compared with wild-type AZIN1. Moreover, edited AZIN1 impaired antizyme-mediated proteasomal degradation of the oncoproteins ornithine decarboxylase 1 (ODC1) and cyclin D1 (CCND1), thus stimulating retinoblastoma (RB) phosphorylation and cell-cycle entry in xenograft-derived tumor cells. These results establish liver-specific RNA editing of AZIN1 as an oncogenic event that modulates AZIN1 protein function and drives tumor initiation and progression in HCC.
- ©2013 American Association for Cancer Research.
Volume 3, Issue 3
