Journal
CELL REPORTS
Volume 22, Issue 13, Pages 3393-3400Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2018.03.019
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Funding
- NIH [R01CA160331, R01CA163377, R01CA202919, R00CA194318]
- U.S. Department of Defense [OC140632P1, OC150446]
- Ovarian Cancer Research Fund Alliance (OCRFA) [291009]
- Cancer Centre Support Grant (CCSG) [CA010815]
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ARID1A, a subunit of the SWI/SNF complex, is among the most frequently mutated genes across cancer types. ARID1A is mutated in more than 50% of ovarian clear cell carcinomas (OCCCs), diseases that have no effective therapy. Here, we show that ARID1A mutation confers sensitivity to pan-HDAC inhibitors such as SAHA in ovarian cancers. This correlated with enhanced growth suppression induced by the inhibition of HDAC2 activity in ARID1A-mutated cells. HDAC2 interacts with EZH2 in an ARID1A status-dependent manner. HDAC2 functions as a corepressor of EZH2 to suppress the expression of EZH2/ARID1A target tumor suppressor genes such as PIK3IP1 to inhibit proliferation and promote apoptosis. SAHA reduced the growth and ascites of the ARID1A-inactivated OCCCs in both orthotopic and genetic mouse models. This correlated with a significant improvement of survival of mice bearing ARID1A-mutated OCCCs. These findings provided preclinical rationales for repurposing FDA-approved pan-HDAC inhibitors for treating ARID1A-mutated cancers.
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