ARID1A Deficiency Promotes Colorectal Cancer via Enhancer Dysregulation

Inactivating mutations in the SWI/SNF chromatin remodeling complex subunit ARID1A occur frequently in multiple tumor types, but the mechanism by which these mutations promote tumorigenesis is not understood. Mathur and colleagues developed a mouse model of inducible Arid1a inactivation and found that Arid1a loss resulted in the development of nodular and polypoid tumors in the colon, not the small intestine as in some other mouse models, that recapitulated human invasive colon adenocarcinoma. Further, specific inactivation of Arid1a in the intestinal epithelium also resulted in adenocarcinoma, indicating that epithelial Arid1a deficiency is a driver of colon tumorigenesis. Human colorectal cancer can be initiated by inactivation of the APC tumor suppressor and disruption of downstream β-catenin signaling, but the tumors driven by ARID1A deficiency displayed functional APC, suggesting that an alternative mechanism drives these tumors. ARID1A is mutually exclusive to ARID1B in SWI/SNF complexes, and, although ARID1A deficiency alone only enhanced invasiveness and did not alter cellular proliferation of human colorectal cancer cell lines, combined depletion of ARID1A and ARID1B reduced proliferation. Chromatin immunoprecipitation sequencing revealed that ARID1A loss reduced SWI/SNF complex occupancy at a large majority of SWI/SNF sites. However, ARID1B-containing SWI/SNF complexes remained intact, altogether indicating that in the setting of ARID1A loss, SWI/SNF targeting is altered but residual ARID1B-containing SWI/SNF complex activity is retained. H3K27 acetylation, a mark of active enhancers, was decreased at enhancers that lost SWI/SNF binding in ARID1A-deficient cells, and SWI/SNF loss at enhancers was associated with altered gene expression in vitro and in vivo, especially genes involved in development. In addition to altering the levels of histone modifications at enhancers, ARID1A loss also altered their distribution. The finding that ARID1A deficiency disrupts SWI/SNF-mediated control of enhancers involved in development provides a mechanism by which ARID1A mutations may drive tumorigenesis.

Mathur R, Alver BH, San Roman AK, Wilson BG, Wang X, Agoston AT, et al. ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice. Nat Genet 2016 Dec 12 [Epub ahead of print].