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.
['Karakashev|Sergey|S|', 'Fukumoto|Takeshi|T|', 'Zhao|Bo|B|', 'Lin|Jianhuang|J|', 'Wu|Shuai|S|', 'Fatkhutdinov|Nail|N|', 'Park|Pyoung-Hwa|PH|', 'Semenova|Galina|G|', 'Jean|Stephanie|S|', 'Cadungog|Mark G|MG|', 'Borowsky|Mark E|ME|', 'Kossenkov|Andrew V|AV|', 'Liu|Qin|Q|', 'Zhang|Rugang|R|']
D000970:Antineoplastic Agents D053903:DNA Breaks, Double-Stranded D059766:DNA End-Joining Repair D000071221:Enhancer of Zeste Homolog 2 Protein D004791:Enzyme Inhibitors D005260:Female D059765:Homologous Recombination D006801:Humans D010051:Ovarian Neoplasms D000067856:Poly(ADP-ribose) Polymerase Inhibitors D011484:Protein-Arginine N-Methyltransferases D059767:Recombinational DNA Repair
shieldin homologous recombination (HR) epithelial ovarian cancer CARM1 SWI/SNF BAF155 PARP inhibitors EZH2 inhibitors MAD2L2 (REV7) non-homologous end-joining (NHEJ) polycomb repressive complex 2 (PRC2)