Repurposing Pan-HDAC Inhibitors for ARID1A-Mutated Ovarian Cancer

Takeshi Fukumoto, Pyoung Hwa Park, Shuai Wu, Nail Fatkhutdinov, Sergey Karakashev, Timothy Nacarelli, Andrew V. Kossenkov, David W. Speicher, Stephanie Jean, Lin Zhang, Tian Li Wang, Ie Ming Shih, Jose R. Conejo-Garcia, Benjamin G. Bitler, Rugang Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

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. Fukumoto et al. 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. These findings provided preclinical rationales for repurposing FDA-approved pan-HDAC inhibitors for treating ARID1A-mutated cancers.

Original languageEnglish (US)
Pages (from-to)3393-3400
Number of pages8
JournalCell Reports
Volume22
Issue number13
DOIs
StatePublished - Mar 27 2018

Keywords

  • ARID1A
  • HDAC2
  • SAHA
  • SWI/SNF
  • chromatin remodeling
  • ovarian cancer
  • pan-HDAC inhibitor

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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