Arid1a Has Context-Dependent Oncogenic and Tumor Suppressor Functions in Liver Cancer

Xuxu Sun; Sam C Wang; Yonglong Wei; Xin Luo; Yuemeng Jia; Lin Li; Purva Gopal; Min Zhu; Ibrahim Nassour; Jen-Chieh Chuang; Thomas Maples; Cemre Celen; Liem H Nguyen; Linwei Wu; Shunjun Fu; Weiping Li; Lijian Hui; Feng Tian; Yuan Ji; Shuyuan Zhang; Mahsa Sorouri; Tae Hyun Hwang; Lynda Letzig; Laura James; Zixi Wang; Adam C Yopp; Amit G Singal; Hao Zhu

doi:10.1016/j.ccell.2017.10.007

Arid1a Has Context-Dependent Oncogenic and Tumor Suppressor Functions in Liver Cancer

Cancer Cell. 2017 Nov 13;32(5):574-589.e6. doi: 10.1016/j.ccell.2017.10.007.

Authors

Xuxu Sun¹, Sam C Wang², Yonglong Wei¹, Xin Luo³, Yuemeng Jia¹, Lin Li¹, Purva Gopal⁴, Min Zhu¹, Ibrahim Nassour², Jen-Chieh Chuang¹, Thomas Maples¹, Cemre Celen¹, Liem H Nguyen⁵, Linwei Wu⁶, Shunjun Fu⁷, Weiping Li⁸, Lijian Hui⁹, Feng Tian¹⁰, Yuan Ji¹⁰, Shuyuan Zhang¹, Mahsa Sorouri¹, Tae Hyun Hwang¹¹, Lynda Letzig¹², Laura James¹², Zixi Wang¹, Adam C Yopp¹³, Amit G Singal¹⁴, Hao Zhu¹⁵

Affiliations

¹ Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
² Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
³ Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁴ Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁵ Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁶ Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Organ Transplant Center, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China.
⁷ Organ Transplant Center, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China.
⁸ State Key Laboratory of Cell Biology, Innovation Center for Cell Signaling Network, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
⁹ State Key Laboratory of Cell Biology, Innovation Center for Cell Signaling Network, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
¹⁰ Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
¹¹ Lerner Research Institute, Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH 44195, USA.
¹² Clinical Pharmacology and Toxicology, Arkansas Children's Hospital and Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA.
¹³ Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
¹⁴ Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
¹⁵ Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: hao.zhu@utsouthwestern.edu.

Abstract

ARID1A, an SWI/SNF chromatin-remodeling gene, is commonly mutated in cancer and hypothesized to be tumor suppressive. In some hepatocellular carcinoma patients, ARID1A was highly expressed in primary tumors but not in metastatic lesions, suggesting that ARID1A can be lost after initiation. Mice with liver-specific homozygous or heterozygous Arid1a loss were resistant to tumor initiation while ARID1A overexpression accelerated initiation. In contrast, homozygous or heterozygous Arid1a loss in established tumors accelerated progression and metastasis. Mechanistically, gain of Arid1a function promoted initiation by increasing CYP450-mediated oxidative stress, while loss of Arid1a within tumors decreased chromatin accessibility and reduced transcription of genes associated with migration, invasion, and metastasis. In summary, ARID1A has context-dependent tumor-suppressive and oncogenic roles in cancer.

Keywords: ARID1A; SWI/SNF chromatin-remodeling complex; epigenetics; hepatocellular carcinoma; metastasis; mouse models.

MeSH terms

Animals
Blotting, Western
Carcinogenesis / genetics
Carcinoma, Hepatocellular / genetics*
Carcinoma, Hepatocellular / metabolism
Carcinoma, Hepatocellular / pathology
Cell Line, Tumor
DNA-Binding Proteins / genetics*
DNA-Binding Proteins / metabolism
Gene Expression Profiling / methods
Gene Expression Regulation, Neoplastic
Genes, Tumor Suppressor
Humans
Liver Neoplasms / genetics*
Liver Neoplasms / metabolism
Liver Neoplasms / pathology
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, Knockout
Mice, SCID
Neoplasm Metastasis
Nuclear Proteins / genetics*
Nuclear Proteins / metabolism
Oncogenes / genetics*
RNA Interference
Transcription Factors

Substances

Arid1a protein, mouse
DNA-Binding Proteins
Nuclear Proteins
Transcription Factors

Abstract

MeSH terms

Substances

Grants and funding