Abstract A52: Arid1a exerts context-dependent oncogenic and tumor suppressor functions in liver cancer

Abstract

Abstract ARID1A, an ATP-dependent SWI/SNF chromatin remodeling complex component, is hypothesized to be one of the most commonly mutated tumor suppressors in human cancer. Using mouse liver cancer models, we sought to elucidate the functional consequences of ARID1A gain and loss. Surprisingly, mice with liver-specific Arid1a deficiency were resistant to chemical- and MYC-induced liver carcinogenesis, while ARID1A overexpression accelerated tumorigenesis when combined with a variety of oncogenes, indicating an important role during tumor initiation. Mechanistically, Arid1a promoted tumor initiation by increasing cytochrome P450-mediated oxidative stress. In human HCCs, late ARID1A loss has been observed upon metastatic spread, suggesting that deleterious mutations do occur after tumor initiation. Indeed, both homozygous and heterozygous loss after liver tumor formation in mice were sufficient to drive progression and metastasis. Intriguingly, the Arid1a haploinsufficient state was sufficient to globally increase chromatin occupancy and downregulate metastasis suppressor genes within tumors. In summary, ARID1A can play both tumor-suppressive and oncogenic roles in liver cancer in a temporally dependent manner, explaining the expression and mutation patterns seen in human HCC. Citation Format: Xuxu Sun, Sam Wang, Shuyuan Zhang, Hao Zhu. Arid1a exerts context-dependent oncogenic and tumor suppressor functions in liver cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A52.