Format

Send to

Choose Destination
Cell Rep. 2018 Mar 27;22(13):3393-3400. doi: 10.1016/j.celrep.2018.03.019.

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

Author information

1
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA.
2
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA; Kazan Federal University, Kazan, Russia.
3
Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, PA 19104, USA.
4
Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, PA 19104, USA; Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
5
Helen F. Graham Cancer Center & Research Institute, Newark, DE 19713, USA.
6
Department of Obstetrics and Gynecology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
7
Departments of Pathology and Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
8
Department of Immunology, Moffitt Cancer Center, Tampa, FL 33612, USA.
9
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA. Electronic address: benjamin.bitler@ucdenver.edu.
10
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA. Electronic address: rzhang@wistar.org.

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.

KEYWORDS:

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

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center