Repurposing Pan-HDAC Inhibitors for ARID1A-Mutated Ovarian Cancer
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...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2018-03-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124718303486 |
| _version_ | 1818969969734451200 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Takeshi Fukumoto |
| collection | DOAJ |
| description | 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 |
| first_indexed | 2024-12-20T14:29:02Z |
| format | Article |
| id | doaj.art-c03c4b3064504442808ca962aa2f53e5 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-20T14:29:02Z |
| publishDate | 2018-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-c03c4b3064504442808ca962aa2f53e52022-12-21T19:37:42ZengElsevierCell Reports2211-12472018-03-01221333933400Repurposing Pan-HDAC Inhibitors for ARID1A-Mutated Ovarian CancerTakeshi Fukumoto0Pyoung Hwa Park1Shuai Wu2Nail Fatkhutdinov3Sergey Karakashev4Timothy Nacarelli5Andrew V. Kossenkov6David W. Speicher7Stephanie Jean8Lin Zhang9Tian-Li Wang10Ie-Ming Shih11Jose R. Conejo-Garcia12Benjamin G. Bitler13Rugang Zhang14Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USAGene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USAGene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USAGene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA; Kazan Federal University, Kazan, RussiaGene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USAGene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USACenter for Systems and Computational Biology, The Wistar Institute, Philadelphia, PA 19104, USACenter for Systems and Computational Biology, The Wistar Institute, Philadelphia, PA 19104, USA; Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USAHelen F. Graham Cancer Center & Research Institute, Newark, DE 19713, USADepartment of Obstetrics and Gynecology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USADepartments of Pathology and Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USADepartments of Pathology and Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USADepartment of Immunology, Moffitt Cancer Center, Tampa, FL 33612, USAGene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA; Corresponding authorGene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA; Corresponding authorSummary: 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 remodelinghttp://www.sciencedirect.com/science/article/pii/S2211124718303486 |
| spellingShingle | 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 Repurposing Pan-HDAC Inhibitors for ARID1A-Mutated Ovarian Cancer Cell Reports |
| title | Repurposing Pan-HDAC Inhibitors for ARID1A-Mutated Ovarian Cancer |
| title_full | Repurposing Pan-HDAC Inhibitors for ARID1A-Mutated Ovarian Cancer |
| title_fullStr | Repurposing Pan-HDAC Inhibitors for ARID1A-Mutated Ovarian Cancer |
| title_full_unstemmed | Repurposing Pan-HDAC Inhibitors for ARID1A-Mutated Ovarian Cancer |
| title_short | Repurposing Pan-HDAC Inhibitors for ARID1A-Mutated Ovarian Cancer |
| title_sort | repurposing pan hdac inhibitors for arid1a mutated ovarian cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2211124718303486 |
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