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
Affiliations
Takeshi Fukumoto
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA
Pyoung Hwa Park
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA
Shuai Wu
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA
Nail Fatkhutdinov
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA; Kazan Federal University, Kazan, Russia
Sergey Karakashev
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA
Timothy Nacarelli
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA
Andrew V. Kossenkov
Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, PA 19104, USA
David W. Speicher
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
Stephanie Jean
Helen F. Graham Cancer Center & Research Institute, Newark, DE 19713, USA
Lin Zhang
Department of Obstetrics and Gynecology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
Tian-Li Wang
Departments of Pathology and Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA
Ie-Ming Shih
Departments of Pathology and Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA
Jose R. Conejo-Garcia
Department of Immunology, Moffitt Cancer Center, Tampa, FL 33612, USA
Benjamin G. Bitler
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA; Corresponding author
Rugang Zhang
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA; Corresponding author
Summary: 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. Keywords: ovarian cancer, ARID1A, HDAC2, pan-HDAC inhibitor, SAHA, SWI/SNF, chromatin remodeling
