5 years ago

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

Arid1a Has Context-Dependent Oncogenic and Tumor Suppressor Functions in Liver Cancer
Tae Hyun Hwang, Sam C. Wang, Min Zhu, Jen-Chieh Chuang, Yuan Ji, Shunjun Fu, Liem H. Nguyen, Thomas Maples, Yuemeng Jia, Laura James, Cemre Celen, Xuxu Sun, Amit G. Singal, Adam C. Yopp, Lijian Hui, Lynda Letzig, Linwei Wu, Purva Gopal, Xin Luo, Yonglong Wei, Hao Zhu, Shuyuan Zhang, Feng Tian, Mahsa Sorouri, Zixi Wang, Weiping Li, Lin Li, Ibrahim Nassour


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.

Publisher URL: http://www.cell.com/cancer-cell/fulltext/S1535-6108(17)30460-9

DOI: 10.1016/j.ccell.2017.10.007

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