Original ArticleNUDT21 regulates 3′-UTR length and microRNA-mediated gene silencing in hepatocellular carcinoma

•NUDT21 is decreased in hepatocellular carcinoma.•NUDT21 co-localizes with AGO2 in P/GW body.•NUDT21 elongates the 3′-UTR and promotes the miRNA-mediated gene silencing.•NUDT21 protects miRNA binding sites and enhances the AGO2-mRNA binding.•NUDT21 works as a tumor suppressor gene, which inhibits cell growth.

Recent studies have shown that several microRNAs (miRNAs) are involved in hepatocellular carcinoma (HCC) tumorigenesis and metastasis; however, the mechanisms responsible for the differences in the functions of these miRNAs in liver cancer remain a mystery. In our previous study, we identified NUDT21 as an interaction partner of argonaute 2 (AGO2). NUDT21 has been reported to be involved in alternative polyadenylation (APA); thus, the interaction between NUDT21 and AGO2 may be a key component of the crosstalk between APA and miRNA-mediated gene silencing in HCC. Our data showed that NUDT21 expression was decreased in HCC. Moreover, our results showed that NUDT21 co-localized with AGO2 in P/GW bodies in normal liver cells; however, this co-localization was diminished in cancer cells. Functional studies showed that NUDT21 elongated the 3′-UTR of mRNA and enhanced the efficiency of miRNA-mediated gene silencing by increasing the efficiency of AGO2-mRNA binding, which played an important role in cell proliferation. In summary, loss of NUDT21 shortened the 3′-UTR of various oncogenes in HCC cells. The shorter 3′-UTR contained less miRNA binding sites, which enabled the oncogenes to evade miRNA regulation and become overexpressed in HCC, leading to unregulated cancer cell proliferation.