| Literature DB >> 32004442 |
Sergey Karakashev1, Takeshi Fukumoto1, Bo Zhao1, Jianhuang Lin1, Shuai Wu1, Nail Fatkhutdinov1, Pyoung-Hwa Park1, Galina Semenova1, Stephanie Jean2, Mark G Cadungog2, Mark E Borowsky2, Andrew V Kossenkov1, Qin Liu3, Rugang Zhang4.
Abstract
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.Entities:
Keywords: BAF155; CARM1; EZH2 inhibitors; MAD2L2 (REV7); PARP inhibitors; SWI/SNF; epithelial ovarian cancer; homologous recombination (HR); non-homologous end-joining (NHEJ); polycomb repressive complex 2 (PRC2); shieldin
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Year: 2020 PMID： 32004442 PMCID： PMC7155421 DOI： 10.1016/j.ccell.2019.12.015
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743