Unknown

Dataset Information

0

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.

SUBMITTER: Fukumoto T 

PROVIDER: S-EPMC5903572 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

altmetric image

Publications


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-d  ...[more]

Similar Datasets

| S-EPMC5541905 | biostudies-literature
| S-EPMC10527942 | biostudies-literature
| S-EPMC8198755 | biostudies-literature
| S-EPMC7663919 | biostudies-literature
| S-EPMC6747090 | biostudies-other
| S-EPMC6095834 | biostudies-literature
| S-EPMC6175882 | biostudies-literature
| S-EPMC6627993 | biostudies-literature
| S-EPMC7734570 | biostudies-literature
2017-07-14 | GSE84405 | GEO