
Repurposing Pan-HDAC Inhibitors for ARID1A-Mutated Ovarian Cancer.
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 co-repressor 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.
Duke Scholars
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Related Subject Headings
- Xenograft Model Antitumor Assays
- Transcription Factors
- Ovarian Neoplasms
- Nuclear Proteins
- Mutation
- Mice, Transgenic
- Mice, Inbred C57BL
- Mice
- Humans
- Histone Deacetylase Inhibitors
Citation

Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Xenograft Model Antitumor Assays
- Transcription Factors
- Ovarian Neoplasms
- Nuclear Proteins
- Mutation
- Mice, Transgenic
- Mice, Inbred C57BL
- Mice
- Humans
- Histone Deacetylase Inhibitors