Repurposing Pan-HDAC Inhibitors for ARID1A-Mutated Ovarian Cancer.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Fukumoto, T; Park, PH; Wu, S; Fatkhutdinov, N; Karakashev, S; Nacarelli, T; Kossenkov, AV; Speicher, DW; Jean, S; Zhang, L; Wang, T-L; Shih, I-M; Conejo-Garcia, JR; Bitler, BG; Zhang, R

Published Date

  • March 27, 2018

Published In

Volume / Issue

  • 22 / 13

Start / End Page

  • 3393 - 3400

PubMed ID

  • 29590609

Pubmed Central ID

  • PMC5903572

Electronic International Standard Serial Number (EISSN)

  • 2211-1247

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2018.03.019


  • eng

Conference Location

  • United States