EZH2 Inhibition Sensitizes CARM1-High, Homologous Recombination Proficient Ovarian Cancers to PARP Inhibition
In response to DNA double-strand breaks, MAD2L2-containing shieldin complex plays a critical role in the choice between homologous recombination (HR) and non-homologous end-joining (NHEJ)-mediated repair. Here we show that EZH2 inhibition upregulates MAD2L2 and sensitizes HR-proficient epithelial ovarian cancer (EOC) to poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor in a CARM1-dependent manner. CARM1 promotes MAD2L2 silencing by driving the switch from the SWI/SNF complex to EZH2 through methylating the BAF155 subunit of the SWI/SNF complex on the MAD2L2 promoter. EZH2 inhibition upregulates MAD2L2 to decrease DNA end resection, which increases NHEJ and chromosomal abnormalities, ultimately causing mitotic catastrophe in PARP inhibitor treated HR-proficient cells. Significantly, EZH2 inhibitor sensitizes CARM1-high, but not CARM-low, EOCs to PARP inhibitors in both orthotopic and patient-derived xenografts.
Journal
Cancer CellAuthors
Funding
Purchase of a PerkinElmer IVIS SpectrumCT Imaging SystemAnimal Shared ResourceProject 3: Investigating new treatment approaches based on DNA repair vulnerability in ARID1A mutated type I ovarian cancerIntegrative Approach to Comprehensive Analysis of High Throughput Data on a Cancer Center LevelMechanistic basis and therapeutic strategies for ARID1A mutation in ovarian cancerSynthetic lethality based combination approaches to ARID1A mutation in ovarian cancerChromatin basis of cellular senescence and its implication in epithelial ovarian cancerTargeting EZH2 in CARM1-expressing epithelial ovarian cancerAstraZeneca FundingHonorable Tina Brozman Foundation FundingOvarian Cancer Research Alliance FundingProject 3: Investigating new treatment approaches based on DNA repair vulnerability in ARID1A mutated type I ovarian cancerChromatin basis of cellular senescence and its implication in epithelial ovarian cancerTargeting EZH2 in CARM1-expressing epithelial ovarian cancerMechanistic basis and therapeutic strategies for ARID1A mutation in ovarian cancerSynthetic lethality based combination approaches to ARID1A mutation in ovarian cancerIntegrative Approach to Comprehensive Analysis of High Throughput Data on a Cancer Center LevelU.S. Department of Defense Grant OC150446U.S. Department of Defense Grant OC180109American Association for Cancer Research Funding