Phosphorylation of UHRF2 affects malignant phenotypes of HCC and HBV replication by blocking DHX9 ubiquitylation
作者全名："Wu, Kejia; Zhang, Yiqi; Liu, Yuxin; Li, Qingxiu; Chen, Yong; Chen, Juan; Duan, Changzhu"
作者地址："[Wu, Kejia; Zhang, Yiqi; Liu, Yuxin; Li, Qingxiu; Duan, Changzhu] Chongqing Med Univ, Mol Med & Canc Res Ctr, Dept Cell Biol & Med Genet, Chongqing 400016, Peoples R China; [Chen, Yong] Chongqing Med Univ, Affiliated Hosp 1, Dept Hepatobillary Surg, Chongqing 400016, Peoples R China; [Chen, Juan] Chongqing Med Univ, Affiliated Hosp 2, Inst Viral Hepatitis, Dept Infect Dis,Key Lab Mol Biol Infect Dis, Chongqing 400016, Peoples R China"
通信作者："Duan, CZ (通讯作者)，Chongqing Med Univ, Mol Med & Canc Res Ctr, Dept Cell Biol & Med Genet, Chongqing 400016, Peoples R China."
来源：CELL DEATH DISCOVERY
ESI学科分类：MOLECULAR BIOLOGY & GENETICS
摘要："Hepatitis B virus (HBV) infection is one of main contributors to poor prognosis and rapid progression of hepatocellular cancer (HCC). We previously identified the important role of the phosphorylation of ubiquitin-like with PHD and ring finger domains (UHRF2) in HBV-associated HCC. In this study we identify upregulated UHRF2 protein levels in HBV-associated HCC cells and tissues. UHRF2 overexpression promotes the viability, proliferation, migration and invasiveness of HBV-positive HCC cell lines, and enhances HBV DNA replication. To obtain a comprehensive understanding of the interaction networks of UHRF2 and their underlying mechanism, this study suggests that UHRF2 facilitates the ubiquitin-proteasome-mediated proteolysis of DExD/H (Asp-Glu-Ala-His) -box helicase enzyme 9 (DHX9). However, phosphorylation of UHRF2 by HBx at S643 inhibits E3 ubiquitin ligase activity of UHRF2 and improves DHX9 protein stability. Furthermore, results suggest that HBx promotes phosphorylation of UHRF2 by the ETS1-CDK2 axis through the downregulation of miR-222-3p in HBV-associated HCC specimens and cells. Our findings suggest that HBx-induced phosphorylation of UHRF2 S643 acts as a ""switch"" in HBV-associated HCC oncogenesis, activating the positive feedback between phosphorylated UHRF2 and HBV, provide evidence that UHRF2 is a new regulator and a potential prognostic indicator of poor prognosis for HBV-associated HCC."