Genes encoding subunits of SWI/SNF (BAF) chromatin remodeling complexes are collectively mutated in ~20% of all human cancers, but the mechanism by which these mutations promote tumorigenesis is unclear. In this study, we investigate the tumor suppressor role of ARID1A, the subunit of SWI/SNF complexes that is the most frequent target of mutations. We develop an inducible Arid1a-knockout mouse model and find that mice develop invasive ARID1A-deficient colon adenocarcinoma. These cancers show prominent mucinous differentiation and tumor-infiltrating lymphocytes, features associated particularly with microsatellite-instable (MSI) human colorectal cancer - the subtype with the highest frequency of inactivating ARID1A mutations (37-39%). Although deregulation of Wnt signaling components (APC/β-catenin) is commonly utilized to model intestinal tumorigenesis, Arid1a-knockout mice reflect human colorectal cancer with greater accuracy. These mice do not show deregulation of Wnt signaling components, thus demonstrating a novel pathway to colon tumorigenesis that is independent of established models. Chromatin immunoprecipitation sequencing reveals that SWI/SNF complexes are targeted primarily to enhancers, where they function in coordination with transcription factors to activate gene expression. ARID1A loss impairs the targeting of SWI/SNF complexes to thousands of enhancers, which subsequently lose activity - showing reduced levels of H3K27ac and expression of nearest genes. Residual SWI/SNF complexes in ARID1A-deficient cells bind enhancers that remain active; these complexes contain ARID1B, the subunit that is mutually exclusive with ARID1A and has been identified as a therapeutic target in ARID1A-deficient cancers. Enhancers associated with developmental gene expression programs are most affected by ARID1A loss, both in the mouse colonic epithelium and in human colon cancer cells. Collectively, these findings represent an advance in colon cancer modeling and implicate enhancer-mediated gene regulation as the principal tumor suppressor function of ARID1A.
Citation Format: Radhika Mathur, Burak H. Alver, Adrianna K. San Roman, Boris G. Wilson, Xiaofeng Wang, Agoston T. Agoston, Peter Park, Ramesh Shivdasani, Charles W. Roberts. ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-286. doi:10.1158/1538-7445.AM2017-LB-286