EZH2抑制使CARM1高表达卵巢癌对PARP抑制敏感
2020-03-01   阅读:296   来源:细胞

EZH2抑制能够使CARM1高表达且擅长同源重组修复的卵巢癌对PARP抑制敏感,这一成果由美国威斯塔研究所Rugang Zhang团队近日取得。该研究于2020年2月10日发表于国际一流学术期刊《癌细胞》。

研究人员表示,通过响应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)两种修复方式选择中起关键作用。

研究人员发现,EZH2抑制上调MAD2L2并使擅长HR修复的上皮性卵巢癌(EOC)对CARM1依赖性的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BAF155亚基甲基化来促进从SWI/SNF复合物向EZH2的转换,从而使得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抑制剂处理的擅长HR细胞中引起有丝分裂缺陷。

值得注意的是,在原位和患者来源的荷瘤中,EZH2抑制剂会使CARM1高表达的荷瘤对PPAR抑制剂敏感,但CARM低表达的则不敏感。

附:英文原文

Title: EZH2 Inhibition Sensitizes CARM1-High, Homologous Recombination Proficient Ovarian Cancers to PARP Inhibition

Author: Sergey Karakashev, Takeshi Fukumoto, Bo Zhao, Jianhuang Lin, Shuai Wu, Nail Fatkhutdinov, Pyoung-Hwa Park, Galina Semenova, Stephanie Jean, Mark G. Cadungog, Mark E. Borowsky, Andrew V. Kossenkov, Qin Liu, Rugang Zhang

Issue&Volume: January 30, 2020

Abstract: In response to DNA double-strand breaks, MAD2L2-containing shieldin complex playsa critical role in the choice between homologous recombination (HR) and non-homologousend-joining (NHEJ)-mediated repair. Here we show that EZH2 inhibition upregulatesMAD2L2 and sensitizes HR-proficient epithelial ovarian cancer (EOC) to poly(adenosinediphosphate-ribose) polymerase (PARP) inhibitor in a CARM1-dependent manner. CARM1promotes MAD2L2 silencing by driving the switch from the SWI/SNF complex to EZH2 through methylatingthe BAF155 subunit of the SWI/SNF complex on the MAD2L2 promoter. EZH2 inhibition upregulates MAD2L2 to decrease DNA end resection, whichincreases NHEJ and chromosomal abnormalities, ultimately causing mitotic catastrophein PARP inhibitor treated HR-proficient cells. Significantly, EZH2 inhibitor sensitizesCARM1-high, but not CARM-low, EOCs to PARP inhibitors in both orthotopic and patient-derivedxenografts.

DOI: 10.1016/j.ccell.2019.12.015

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