Abstract
Abstract It is unclear if regenerative capacity can be dissociated from cancer risk, a question that is highly relevant for liver carcinogenesis. Frequent SWI/SNF and Arid1a loss-of-function mutations suggest tumor suppressive roles, but the functional impact of these mutations in tissue homeostasis and cancer is unclear. Mice without Arid1a possessed improved healing abilities after an array of injuries. After liver resection, chemical hepatocyte injury, and toxic bile duct injury, Arid1a deficient livers exhibited increased regeneration, reduced tissue damage, and improved organ function. Moreover, global homozygous Arid1a loss potentiated soft tissue healing after ear hole punch and hematopoietic recovery after irradiation. The chromatin state as reprogrammed by Arid1a loss restricted access to promoters by lineage-specific transcription factors that ordinarily suppress cell cycle reentry, thus increasing regeneration after injury. Intriguingly, the homozygous Arid1a deficient state protected mice from chemical injury induced hepatocellular carcinoma (HCC) and extended survival in a MYC-driven hepatoblastoma model. Since Arid1a mutations are most frequently heterozygous in human HCC genome studies, we examined the haploinsufficient state in these mouse models and observed accelerated carcinogenesis and metastasis. Transcriptome analysis identified dysregulated differentiation, proliferation, and metastasis programs. These models show that full deletion of Arid1a can enhance mammalian regeneration without increasing cancer risk, but that Arid1a’s tumor suppressor functions are highly sensitive to dose. This abstract is also presented as Poster A16. Citation Format: Xuxu Sun, Sam Wang, Thomas Maples, Lin Li, Liem Nguyen, Jen-Chieh Chuang, Mahsa Sorouri, Shuyuan Zhang, Linwei Wu, Cemre Celen, Hao Zhu. The SWI/SNF component Arid1a regulates regenerative capacity and carcinogenesis in a dose-dependent fashion. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr PR02.
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