Sun Xuxu, Wang Sam C, Wei Yonglong, Luo Xin, Jia Yuemeng, Li Lin, Gopal Purva, Zhu Min, Nassour Ibrahim, Chuang Jen-Chieh, Maples Thomas, Celen Cemre, Nguyen Liem H, Wu Linwei, Fu Shunjun, Li Weiping, Hui Lijian, Tian Feng, Ji Yuan, Zhang Shuyuan, Sorouri Mahsa, Hwang Tae Hyun, Letzig Lynda, James Laura, Wang Zixi, Yopp Adam C, Singal Amit G, Zhu Hao
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.
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.
Cancer Cell. 2017 Nov 13;32(5):574-589.e6. doi: 10.1016/j.ccell.2017.10.007.
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.
ARID1A是一种SWI/SNF染色质重塑基因，在癌症中常发生突变，并被认为具有肿瘤抑制作用。在一些肝细胞癌患者中，ARID1A在原发性肿瘤中高表达，但在转移灶中不表达，这表明ARID1A在肿瘤发生后可能会丢失。肝脏特异性纯合或杂合缺失Arid1a的小鼠对肿瘤起始具有抗性，而ARID1A过表达则加速肿瘤起始。相反，在已建立的肿瘤中纯合或杂合缺失Arid1a会加速肿瘤进展和转移。从机制上讲，Arid1a功能的获得通过增加CYP450介导的氧化应激来促进肿瘤起始，而肿瘤内Arid1a的缺失则降低了染色质可及性，并减少了与迁移、侵袭和转移相关基因的转录。总之，ARID1A在癌症中具有依赖于背景的肿瘤抑制和致癌作用。
