| Autor: |
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 |
| Jazyk: |
angličtina |
| Rok vydání: |
2018 |
| Předmět: |
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| Zdroj: |
Cell Reports, Vol 22, Iss 13, Pp 3393-3400 (2018) |
| Druh dokumentu: |
article |
| ISSN: |
2211-1247 |
| DOI: |
10.1016/j.celrep.2018.03.019 |
| Popis: |
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 |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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