GSE107201
Synthetic lethality between ARID1A mutation and HDAC2 inhibition in ovarian cancer
ARID1A, encoding a subunit of the SWI/SNF chromatin remodeling complex, is the most frequently mutated epigenetic regulators in human cancers.  ARID1A is mutated in over 50% ovarian clear cell carcinoma, a disease currently has no effective therapy.  Here we show that ARID1A-mutated ovarian cancer cells are selectively sensitive to inhibition of HDAC2 activity. HDAC2 interacts with EZH2 in an ARID1A status dependent manner. HDAC2 knockdown inhibits the growth of ARID1A inactivated by not proficient ovarian cancer cells. HDAC2 functions as a co-repressor of EZH2 to suppress the expression of EZH2/ARID1A target tumor suppressor genes such as PIK3IP1, an inhibitor of PI3K/AKT signaling, to inhibit proliferation and promote apoptosis.  Indeed, a FDA-approved pan-HDAC inhibitor suberoylannilide hydroxamine (SAHA) significantly suppressed the growth and reduced the ascites of the ARID1A-inactivated ovarian cancers in both orthotopic and genetic mouse models.   This correlated with a significant improvement of survival of mice bearing ARID1A-mutated ovarian cancers. Overall design: HDAC2 wild type and shRNA knockdown samples assayed by RNA-seq