The Ubiquitin E3 Ligase TRIM21 Promotes Hepatocarcinogenesis by Suppressing the p62-Keap1-Nrf2 Antioxidant PathwaySummary
Background and Aims: TRIM21 is a ubiquitin E3 ligase that is implicated in numerous biological processes including immune response, cell metabolism, redox homeostasis, and cancer development. We recently reported that TRIM21 can negatively regulate the p62-Keap1-Nrf2 antioxidant pathway by ubiquityl...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X21000138 |
| _version_ | 1818942616759173120 |
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| author | Fang Wang Ye Zhang Jianliang Shen Bin Yang Weiwei Dai Junrong Yan Sara Maimouni Heineken Q. Daguplo Sara Coppola Yingtang Gao Yijun Wang Zhi Du Kesong Peng Hui Liu Qin Zhang Fei Tang Peng Wang Shenglan Gao Yongbo Wang Wen-Xing Ding Grace Guo Fengmei Wang Wei-Xing Zong |
| author_facet | Fang Wang Ye Zhang Jianliang Shen Bin Yang Weiwei Dai Junrong Yan Sara Maimouni Heineken Q. Daguplo Sara Coppola Yingtang Gao Yijun Wang Zhi Du Kesong Peng Hui Liu Qin Zhang Fei Tang Peng Wang Shenglan Gao Yongbo Wang Wen-Xing Ding Grace Guo Fengmei Wang Wei-Xing Zong |
| author_sort | Fang Wang |
| collection | DOAJ |
| description | Background and Aims: TRIM21 is a ubiquitin E3 ligase that is implicated in numerous biological processes including immune response, cell metabolism, redox homeostasis, and cancer development. We recently reported that TRIM21 can negatively regulate the p62-Keap1-Nrf2 antioxidant pathway by ubiquitylating p62 and prevents its oligomerization and protein sequestration function. As redox homeostasis plays a pivotal role in many cancers including liver cancer, we sought to determine the role of TRIM21 in hepatocarcinogenesis. Methods: We examined the correlation between TRIM21 expression and the disease using publicly available data sets and 49 cases of HCC clinical samples. We used TRIM21 genetic knockout mice to determine how TRIM21 ablation impact HCC induced by the carcinogen DEN plus phenobarbital (PB). We explored the mechanism that loss of TRIM21 protects cells from DEN-induced oxidative damage and cell death. Results: There is a positive correlation between TRIM21 expression and HCC. Consistently, TRIM21-knockout mice are resistant to DEN-induced hepatocarcinogenesis. This is accompanied by decreased cell death and tissue damage upon DEN treatment, hence reduced hepatic tissue repair response and compensatory proliferation. Cells deficient in TRIM21 display enhanced p62 sequestration of Keap1 and are protected from DEN-induced ROS induction and cell death. Reconstitution of wild-type but not the E3 ligase-dead and the p62 binding-deficient mutant TRIM21 impedes the protection from DEN-induced oxidative damage and cell death in TRIM21-deficient cells. Conclusions: Increased TRIM21 expression is associated with human HCC. Genetic ablation of TRIM21 leads to protection against oxidative hepatic damage and decreased hepatocarcinogenesis, suggesting TRIM21 as a preventive and therapeutic target. |
| first_indexed | 2024-12-20T07:14:16Z |
| format | Article |
| id | doaj.art-e9f19518083a444bbbc82d5a5d9a8ae1 |
| institution | Directory Open Access Journal |
| issn | 2352-345X |
| language | English |
| last_indexed | 2024-12-20T07:14:16Z |
| publishDate | 2021-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj.art-e9f19518083a444bbbc82d5a5d9a8ae12022-12-21T19:48:50ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2021-01-0111513691385The Ubiquitin E3 Ligase TRIM21 Promotes Hepatocarcinogenesis by Suppressing the p62-Keap1-Nrf2 Antioxidant PathwaySummaryFang Wang0Ye Zhang1Jianliang Shen2Bin Yang3Weiwei Dai4Junrong Yan5Sara Maimouni6Heineken Q. Daguplo7Sara Coppola8Yingtang Gao9Yijun Wang10Zhi Du11Kesong Peng12Hui Liu13Qin Zhang14Fei Tang15Peng Wang16Shenglan Gao17Yongbo Wang18Wen-Xing Ding19Grace Guo20Fengmei Wang21Wei-Xing Zong22Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin Third Central Hospital, Tianjin, China; Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New JerseyTianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin Third Central Hospital, Tianjin, China; Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New JerseyDepartment of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New JerseyTianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin Third Central Hospital, Tianjin, ChinaDepartment of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New JerseyDepartment of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New JerseyDepartment of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New JerseyDepartment of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New JerseyDepartment of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New JerseyTianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin Third Central Hospital, Tianjin, ChinaTianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin Third Central Hospital, Tianjin, ChinaTianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin Third Central Hospital, Tianjin, ChinaDepartment of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, ChinaTianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin Third Central Hospital, Tianjin, ChinaTianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin Third Central Hospital, Tianjin, ChinaTianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin Third Central Hospital, Tianjin, ChinaTianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin Third Central Hospital, Tianjin, ChinaDepartment of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, ChinaDepartment of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, ChinaDepartment of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KansasDepartment of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New JerseyTianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin Third Central Hospital, Tianjin, ChinaDepartment of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey; Cancer Metabolism and Growth Program, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey; Reprint Requests Address requests for reprints to: Wei-Xing Zong, PhD, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers-The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 08854.fax: (732) 445-0687.Background and Aims: TRIM21 is a ubiquitin E3 ligase that is implicated in numerous biological processes including immune response, cell metabolism, redox homeostasis, and cancer development. We recently reported that TRIM21 can negatively regulate the p62-Keap1-Nrf2 antioxidant pathway by ubiquitylating p62 and prevents its oligomerization and protein sequestration function. As redox homeostasis plays a pivotal role in many cancers including liver cancer, we sought to determine the role of TRIM21 in hepatocarcinogenesis. Methods: We examined the correlation between TRIM21 expression and the disease using publicly available data sets and 49 cases of HCC clinical samples. We used TRIM21 genetic knockout mice to determine how TRIM21 ablation impact HCC induced by the carcinogen DEN plus phenobarbital (PB). We explored the mechanism that loss of TRIM21 protects cells from DEN-induced oxidative damage and cell death. Results: There is a positive correlation between TRIM21 expression and HCC. Consistently, TRIM21-knockout mice are resistant to DEN-induced hepatocarcinogenesis. This is accompanied by decreased cell death and tissue damage upon DEN treatment, hence reduced hepatic tissue repair response and compensatory proliferation. Cells deficient in TRIM21 display enhanced p62 sequestration of Keap1 and are protected from DEN-induced ROS induction and cell death. Reconstitution of wild-type but not the E3 ligase-dead and the p62 binding-deficient mutant TRIM21 impedes the protection from DEN-induced oxidative damage and cell death in TRIM21-deficient cells. Conclusions: Increased TRIM21 expression is associated with human HCC. Genetic ablation of TRIM21 leads to protection against oxidative hepatic damage and decreased hepatocarcinogenesis, suggesting TRIM21 as a preventive and therapeutic target.http://www.sciencedirect.com/science/article/pii/S2352345X21000138TRIM21Hepatocellular Carcinomap62Nrf2Diethylnitrosamine |
| spellingShingle | Fang Wang Ye Zhang Jianliang Shen Bin Yang Weiwei Dai Junrong Yan Sara Maimouni Heineken Q. Daguplo Sara Coppola Yingtang Gao Yijun Wang Zhi Du Kesong Peng Hui Liu Qin Zhang Fei Tang Peng Wang Shenglan Gao Yongbo Wang Wen-Xing Ding Grace Guo Fengmei Wang Wei-Xing Zong The Ubiquitin E3 Ligase TRIM21 Promotes Hepatocarcinogenesis by Suppressing the p62-Keap1-Nrf2 Antioxidant PathwaySummary Cellular and Molecular Gastroenterology and Hepatology TRIM21 Hepatocellular Carcinoma p62 Nrf2 Diethylnitrosamine |
| title | The Ubiquitin E3 Ligase TRIM21 Promotes Hepatocarcinogenesis by Suppressing the p62-Keap1-Nrf2 Antioxidant PathwaySummary |
| title_full | The Ubiquitin E3 Ligase TRIM21 Promotes Hepatocarcinogenesis by Suppressing the p62-Keap1-Nrf2 Antioxidant PathwaySummary |
| title_fullStr | The Ubiquitin E3 Ligase TRIM21 Promotes Hepatocarcinogenesis by Suppressing the p62-Keap1-Nrf2 Antioxidant PathwaySummary |
| title_full_unstemmed | The Ubiquitin E3 Ligase TRIM21 Promotes Hepatocarcinogenesis by Suppressing the p62-Keap1-Nrf2 Antioxidant PathwaySummary |
| title_short | The Ubiquitin E3 Ligase TRIM21 Promotes Hepatocarcinogenesis by Suppressing the p62-Keap1-Nrf2 Antioxidant PathwaySummary |
| title_sort | ubiquitin e3 ligase trim21 promotes hepatocarcinogenesis by suppressing the p62 keap1 nrf2 antioxidant pathwaysummary |
| topic | TRIM21 Hepatocellular Carcinoma p62 Nrf2 Diethylnitrosamine |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X21000138 |
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