ARIH2 regulates the proliferation, DNA damage and chemosensitivity of gastric cancer cells by reducing the stability of p21 via ubiquitination

Abstract Ariadne homolog 2 (ARIH2) is a key member of the RING-between-RING (RBR) E3 ligase family, which is characterized by an RBR domain involved in the polyubiquitination process. However, the molecular mechanism and biological function of ARIH2 in the pathogenesis of gastric cancer remain unclear. In this paper, we found that high ARIH2 expression is correlated with poor prognosis in gastric cancer patients and that ARIH2 can significantly promote the proliferation of gastric cancer cells. The effect of ARIH2 knockdown on colony formation and tumorigenesis of gastric cancer cells was also shown both in vivo and in vitro. Further mechanistic investigations revealed that ARIH2 interacts with p21 and induces p21 ubiquitination, and that the K48 residue of ubiquitin and the K161 residue of p21 play key roles in ARIH2-mediated p21 ubiquitination. We identified ARIH2 as an E3 ligase of p21 by an in vitro ubiquitination assay. In addition, ARIH2 knockdown induced DNA damage, and then induced cell apoptosis and regulated the chemosensitivity of gastric cancer cells after combined treatment with 5-fluorouracil. Generally, our results indicated that ARIH2 promotes the proliferation of gastric cancer cells and regulates p21 expression. These data demonstrate the need to further evaluate the potential therapeutic implications of ARIH2 in gastric cancer.