Targeting USP9X–AMPK Axis in ARID1A-Deficient Hepatocellular CarcinomaSummary
Background & Aims: Hepatocellular carcinoma (HCC) is a highly heterogeneous solid tumor with high morbidity and mortality. AT-rich interaction domain 1A (ARID1A) accounts for up to 10% of mutations in liver cancer, however, its role in HCC remains controversial, and no targeted therapy has b...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X22000613 |
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| author | Feng-Kun Zhang Qian-Zhi Ni Kang Wang Hui-Jun Cao Dong-Xian Guan Er-Bin Zhang Ning Ma Yi-Kang Wang Qian-Wen Zheng Sheng Xu Bing Zhu Tian-Wei Chen Ji Xia Xiao-Song Qiu Xu-Fen Ding Hao Jiang Lin Qiu Xiang Wang Wei Chen Shu-Qun Cheng Dong Xie Jing-Jing Li |
| author_facet | Feng-Kun Zhang Qian-Zhi Ni Kang Wang Hui-Jun Cao Dong-Xian Guan Er-Bin Zhang Ning Ma Yi-Kang Wang Qian-Wen Zheng Sheng Xu Bing Zhu Tian-Wei Chen Ji Xia Xiao-Song Qiu Xu-Fen Ding Hao Jiang Lin Qiu Xiang Wang Wei Chen Shu-Qun Cheng Dong Xie Jing-Jing Li |
| author_sort | Feng-Kun Zhang |
| collection | DOAJ |
| description | Background & Aims: Hepatocellular carcinoma (HCC) is a highly heterogeneous solid tumor with high morbidity and mortality. AT-rich interaction domain 1A (ARID1A) accounts for up to 10% of mutations in liver cancer, however, its role in HCC remains controversial, and no targeted therapy has been established. Methods: The expression of ARID1A in clinical samples was examined by Western blot and immunohistochemical staining. ARID1A was knocked out by Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) in HCC cell lines, and the effects of glucose deprivation on cell viability, proliferation, and apoptosis were measured. Mass spectrometry analysis was used to find ARID1A-interacting proteins, and the result was verified by co-immunoprecipitation and Glutathione S Transferase (GST) pull-down. The regulation of ARID1A target gene USP9X was investigated by chromatin immunoprecipitation, Glutathione S Transferase (GST) pull-down, luciferase reporter assay, and so forth. Finally, drug treatments were performed to explore the therapeutic potential of the agents targeting ARID1A-deficient HCC in vitro and in vivo. Results: Our study has shown that ARID1A loss protected cells from glucose deprivation–induced cell death. A mechanism study disclosed that AIRD1A recruited histone deacetylase 1 via its C-terminal region DUF3518 to the promoter of USP9X, resulting in down-regulation of USP9X and its target protein kinase AMP-activated catalytic subunit α2 (PRKAA2). ARID1A knockout and a 1989∗ truncation mutant in HCC abolished this effect, increased the levels of H3K9 and H3K27 acetylation at the USP9X promoter, and up-regulated the expression of USP9X and protein kinase AMP-activated catalytic subunit α2 (PRKAA2), which mediated the adaptation of tumor cells to glucose starvation. Compound C dramatically inhibited the growth of ARID1A-deficient tumors and prolongs the survival of tumor-bearing mice. Conclusions: HCC patients with ARID1A mutation may benefit from synthetic lethal therapy targeting the ubiquitin-specific peptidase 9 X-linked (USP9X)–adenosine 5‘-monophosphate–activated protein kinase (AMPK) axis. |
| first_indexed | 2024-12-12T07:59:21Z |
| format | Article |
| id | doaj.art-6081b48badf6405c9e3e285dc3454d2a |
| institution | Directory Open Access Journal |
| issn | 2352-345X |
| language | English |
| last_indexed | 2024-12-12T07:59:21Z |
| publishDate | 2022-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj.art-6081b48badf6405c9e3e285dc3454d2a2022-12-22T00:32:11ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2022-01-01141101127Targeting USP9X–AMPK Axis in ARID1A-Deficient Hepatocellular CarcinomaSummaryFeng-Kun Zhang0Qian-Zhi Ni1Kang Wang2Hui-Jun Cao3Dong-Xian Guan4Er-Bin Zhang5Ning Ma6Yi-Kang Wang7Qian-Wen Zheng8Sheng Xu9Bing Zhu10Tian-Wei Chen11Ji Xia12Xiao-Song Qiu13Xu-Fen Ding14Hao Jiang15Lin Qiu16Xiang Wang17Wei Chen18Shu-Qun Cheng19Dong Xie20Jing-Jing Li21CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, ChinaCAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China; Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, ChinaDepartment of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, ChinaCAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, ChinaCAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, ChinaCAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, ChinaCAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, ChinaCAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, ChinaCAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China; School of Life Science and Technology, Shanghai Tech University, Shanghai, ChinaCAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, ChinaCAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, ChinaCAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, ChinaCAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, ChinaCAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China; School of Life Science and Technology, Shanghai Tech University, Shanghai, ChinaCAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, ChinaDepartment of Biomedical Informatics, School of Life Sciences, Central South University, Changsha, Hunan, ChinaCAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, ChinaKey Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, ChinaCancer Institute of Integrated Traditional Chinese and Western Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, ChinaDepartment of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, ChinaCAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China; School of Life Science and Technology, Shanghai Tech University, Shanghai, China; National Health Commission Key Laboratory of Food Safety Risk Assessment, China National Center for Food Safety Risk Assessment, Beijing, ChinaCAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China; Correspondence Address correspondence to: Jing-Jing Li, PhD, or Dong Xie, PhD, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, 320 YueYang Road, Shanhgai 200031, China. fax: (86) 21-54920078.Background & Aims: Hepatocellular carcinoma (HCC) is a highly heterogeneous solid tumor with high morbidity and mortality. AT-rich interaction domain 1A (ARID1A) accounts for up to 10% of mutations in liver cancer, however, its role in HCC remains controversial, and no targeted therapy has been established. Methods: The expression of ARID1A in clinical samples was examined by Western blot and immunohistochemical staining. ARID1A was knocked out by Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) in HCC cell lines, and the effects of glucose deprivation on cell viability, proliferation, and apoptosis were measured. Mass spectrometry analysis was used to find ARID1A-interacting proteins, and the result was verified by co-immunoprecipitation and Glutathione S Transferase (GST) pull-down. The regulation of ARID1A target gene USP9X was investigated by chromatin immunoprecipitation, Glutathione S Transferase (GST) pull-down, luciferase reporter assay, and so forth. Finally, drug treatments were performed to explore the therapeutic potential of the agents targeting ARID1A-deficient HCC in vitro and in vivo. Results: Our study has shown that ARID1A loss protected cells from glucose deprivation–induced cell death. A mechanism study disclosed that AIRD1A recruited histone deacetylase 1 via its C-terminal region DUF3518 to the promoter of USP9X, resulting in down-regulation of USP9X and its target protein kinase AMP-activated catalytic subunit α2 (PRKAA2). ARID1A knockout and a 1989∗ truncation mutant in HCC abolished this effect, increased the levels of H3K9 and H3K27 acetylation at the USP9X promoter, and up-regulated the expression of USP9X and protein kinase AMP-activated catalytic subunit α2 (PRKAA2), which mediated the adaptation of tumor cells to glucose starvation. Compound C dramatically inhibited the growth of ARID1A-deficient tumors and prolongs the survival of tumor-bearing mice. Conclusions: HCC patients with ARID1A mutation may benefit from synthetic lethal therapy targeting the ubiquitin-specific peptidase 9 X-linked (USP9X)–adenosine 5‘-monophosphate–activated protein kinase (AMPK) axis.http://www.sciencedirect.com/science/article/pii/S2352345X22000613SWI/SNF ComplexHDAC1Epigenetic |
| spellingShingle | Feng-Kun Zhang Qian-Zhi Ni Kang Wang Hui-Jun Cao Dong-Xian Guan Er-Bin Zhang Ning Ma Yi-Kang Wang Qian-Wen Zheng Sheng Xu Bing Zhu Tian-Wei Chen Ji Xia Xiao-Song Qiu Xu-Fen Ding Hao Jiang Lin Qiu Xiang Wang Wei Chen Shu-Qun Cheng Dong Xie Jing-Jing Li Targeting USP9X–AMPK Axis in ARID1A-Deficient Hepatocellular CarcinomaSummary Cellular and Molecular Gastroenterology and Hepatology SWI/SNF Complex HDAC1 Epigenetic |
| title | Targeting USP9X–AMPK Axis in ARID1A-Deficient Hepatocellular CarcinomaSummary |
| title_full | Targeting USP9X–AMPK Axis in ARID1A-Deficient Hepatocellular CarcinomaSummary |
| title_fullStr | Targeting USP9X–AMPK Axis in ARID1A-Deficient Hepatocellular CarcinomaSummary |
| title_full_unstemmed | Targeting USP9X–AMPK Axis in ARID1A-Deficient Hepatocellular CarcinomaSummary |
| title_short | Targeting USP9X–AMPK Axis in ARID1A-Deficient Hepatocellular CarcinomaSummary |
| title_sort | targeting usp9x ampk axis in arid1a deficient hepatocellular carcinomasummary |
| topic | SWI/SNF Complex HDAC1 Epigenetic |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X22000613 |
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