期刊
NATURE GENETICS
卷 49, 期 2, 页码 296-302出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3744
关键词
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资金
- US National Institutes of Health [R01CA172152, R01DK081113]
- Claudia Adams Barr grant
- Innovation Award from Alex's Lemonade Stand
- US National Institutes of Health predoctoral fellowships [1F31CA199994, 1F31CA180784]
- Pathway to Independence Award from the US National Institutes of Health [K99CA197640]
- Cure AT/RT Now foundation
- Avalanna Fund
- Garrett B. Smith Foundation
- Miles for Mary
- ALSAC/St. Jude
- Lind Family
- NCI Cancer Center Support Grant [P30CA06516]
Genes encoding subunits of SWI/SNF (BAF) chromatin remodeling complexes are collectively mutated in similar to 20% of all human cancers(1,2). 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/beta-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.
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