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EZH2 Inhibition Sensitizes CARM1-High, Homologous Recombination Proficient Ovarian Cancers to PARP Inhibition.
Cancer Cell ( IF 48.8 ) Pub Date : 2020-01-22 , DOI: 10.1016/j.ccell.2019.12.015 Sergey Karakashev 1 , Takeshi Fukumoto 1 , Bo Zhao 1 , Jianhuang Lin 1 , Shuai Wu 1 , Nail Fatkhutdinov 1 , Pyoung-Hwa Park 1 , Galina Semenova 1 , Stephanie Jean 2 , Mark G Cadungog 2 , Mark E Borowsky 2 , Andrew V Kossenkov 1 , Qin Liu 3 , Rugang Zhang 1
Cancer Cell ( IF 48.8 ) Pub Date : 2020-01-22 , DOI: 10.1016/j.ccell.2019.12.015 Sergey Karakashev 1 , Takeshi Fukumoto 1 , Bo Zhao 1 , Jianhuang Lin 1 , Shuai Wu 1 , Nail Fatkhutdinov 1 , Pyoung-Hwa Park 1 , Galina Semenova 1 , Stephanie Jean 2 , Mark G Cadungog 2 , Mark E Borowsky 2 , Andrew V Kossenkov 1 , Qin Liu 3 , Rugang Zhang 1
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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.
中文翻译：
EZH2抑制使高CARM1高同源重组卵巢癌对PARP抑制敏感。
响应DNA双链断裂，含MAD2L2的shieldin复合物在同源重组（HR）和非同源末端连接（NHEJ）介导的修复之间的选择中起关键作用。在这里，我们显示EZH2抑制上调MAD2L2，并以CARM1依赖性方式使HR上皮性卵巢癌（EOC）对聚（腺苷二磷酸核糖）聚合酶（PARP）抑制剂敏感。CARM1通过使MAD2L2启动子上的SWI / SNF复合物的BAF155亚基甲基化来驱动从SWI / SNF复合物向EZH2的转换，从而促进MAD2L2沉默。EZH2抑制上调MAD2L2，以减少DNA末端切除，从而增加NHEJ和染色体异常，最终在PARP抑制剂处理的HR熟练细胞中引起有丝分裂灾难。值得注意的是，EZH2抑制剂能使高CARM1增敏，
更新日期：2020-01-31
中文翻译：
EZH2抑制使高CARM1高同源重组卵巢癌对PARP抑制敏感。
响应DNA双链断裂，含MAD2L2的shieldin复合物在同源重组（HR）和非同源末端连接（NHEJ）介导的修复之间的选择中起关键作用。在这里，我们显示EZH2抑制上调MAD2L2，并以CARM1依赖性方式使HR上皮性卵巢癌（EOC）对聚（腺苷二磷酸核糖）聚合酶（PARP）抑制剂敏感。CARM1通过使MAD2L2启动子上的SWI / SNF复合物的BAF155亚基甲基化来驱动从SWI / SNF复合物向EZH2的转换，从而促进MAD2L2沉默。EZH2抑制上调MAD2L2，以减少DNA末端切除，从而增加NHEJ和染色体异常，最终在PARP抑制剂处理的HR熟练细胞中引起有丝分裂灾难。值得注意的是，EZH2抑制剂能使高CARM1增敏，
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