Phosphorylation of UHRF2 affects malignant phenotypes of HCC and HBV replication by blocking DHX9 ubiquitylation
Abstract 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...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-01-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-023-01323-2 |
| _version_ | 1811176046972633088 |
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| author | Kejia Wu Yiqi Zhang Yuxin Liu Qingxiu Li Yong Chen Juan Chen Changzhu Duan |
| author_facet | Kejia Wu Yiqi Zhang Yuxin Liu Qingxiu Li Yong Chen Juan Chen Changzhu Duan |
| author_sort | Kejia Wu |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-10T19:45:42Z |
| format | Article |
| id | doaj.art-d33221c48fb5470699b7172e4702acc3 |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-04-10T19:45:42Z |
| publishDate | 2023-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-d33221c48fb5470699b7172e4702acc32023-01-29T12:04:24ZengNature Publishing GroupCell Death Discovery2058-77162023-01-019111410.1038/s41420-023-01323-2Phosphorylation of UHRF2 affects malignant phenotypes of HCC and HBV replication by blocking DHX9 ubiquitylationKejia Wu0Yiqi Zhang1Yuxin Liu2Qingxiu Li3Yong Chen4Juan Chen5Changzhu Duan6Department of Cell Biology and Medical Genetics, Molecular Medicine and Cancer Research Center, Chongqing Medical UniversityDepartment of Cell Biology and Medical Genetics, Molecular Medicine and Cancer Research Center, Chongqing Medical UniversityDepartment of Cell Biology and Medical Genetics, Molecular Medicine and Cancer Research Center, Chongqing Medical UniversityDepartment of Cell Biology and Medical Genetics, Molecular Medicine and Cancer Research Center, Chongqing Medical UniversityDepartment of Hepatobillary Surgery, The First Affiliated Hospital, Chongqing Medical UniversityKey Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical UniversityDepartment of Cell Biology and Medical Genetics, Molecular Medicine and Cancer Research Center, Chongqing Medical UniversityAbstract 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.https://doi.org/10.1038/s41420-023-01323-2 |
| spellingShingle | Kejia Wu Yiqi Zhang Yuxin Liu Qingxiu Li Yong Chen Juan Chen Changzhu Duan Phosphorylation of UHRF2 affects malignant phenotypes of HCC and HBV replication by blocking DHX9 ubiquitylation Cell Death Discovery |
| title | Phosphorylation of UHRF2 affects malignant phenotypes of HCC and HBV replication by blocking DHX9 ubiquitylation |
| title_full | Phosphorylation of UHRF2 affects malignant phenotypes of HCC and HBV replication by blocking DHX9 ubiquitylation |
| title_fullStr | Phosphorylation of UHRF2 affects malignant phenotypes of HCC and HBV replication by blocking DHX9 ubiquitylation |
| title_full_unstemmed | Phosphorylation of UHRF2 affects malignant phenotypes of HCC and HBV replication by blocking DHX9 ubiquitylation |
| title_short | Phosphorylation of UHRF2 affects malignant phenotypes of HCC and HBV replication by blocking DHX9 ubiquitylation |
| title_sort | phosphorylation of uhrf2 affects malignant phenotypes of hcc and hbv replication by blocking dhx9 ubiquitylation |
| url | https://doi.org/10.1038/s41420-023-01323-2 |
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