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Nat Genet. 2017 Feb;49(2):296-302. doi: 10.1038/ng.3744. Epub 2016 Dec 12.

ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice.

Author information

1
Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts, USA.
2
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
3
Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA.
4
Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
5
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
6
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
7
Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

Abstract

Genes encoding subunits of SWI/SNF (BAF) chromatin-remodeling complexes are collectively mutated in ∼20% of all human cancers. Although ARID1A is the most frequent target of mutations, the mechanism by which its inactivation promotes tumorigenesis is unclear. Here we demonstrate that Arid1a functions as a tumor suppressor in the mouse colon, but not the small intestine, and that invasive ARID1A-deficient adenocarcinomas resemble human colorectal cancer (CRC). These tumors lack deregulation of APC/β-catenin signaling components, which are crucial gatekeepers in common forms of intestinal cancer. We find that ARID1A normally targets SWI/SNF complexes to enhancers, where they function in coordination with transcription factors to facilitate gene activation. ARID1B preserves SWI/SNF function in ARID1A-deficient cells, but defects in SWI/SNF targeting and control of enhancer activity cause extensive dysregulation of gene expression. These findings represent an advance in colon cancer modeling and implicate enhancer-mediated gene regulation as a principal tumor-suppressor function of ARID1A.

PMID:
27941798
PMCID:
PMC5285448
DOI:
10.1038/ng.3744
[Indexed for MEDLINE]
Free PMC Article

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