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

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.

• Authors: 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
• Journal: Cell reports (Cell Rep) Vol. 22 Issue 13 Pg. 3393-3400 (03 27 2018) ISSN: 2211-1247 [Electronic] United States
• PMID: 29590609 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• ARID1A protein, human
• DNA-Binding Proteins
• Histone Deacetylase Inhibitors
• Nuclear Proteins
• Transcription Factors

Topics

• Animals
• DNA-Binding Proteins
• Drug Repositioning
• Female
• Histone Deacetylase Inhibitors (pharmacology)
• Humans
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Mutation
• Nuclear Proteins (genetics, metabolism)
• Ovarian Neoplasms (drug therapy, genetics, pathology)
• Transcription Factors (genetics, metabolism)
• Xenograft Model Antitumor Assays