EZH2抑制使CARM1高表達(dá)卵巢癌對(duì)PARP抑制敏感
EZH2抑制能夠使CARM1高表達(dá)且擅長同源重組修復(fù)的卵巢癌對(duì)PARP抑制敏感，這一成果由美國威斯塔研究所Rugang Zhang團(tuán)隊(duì)近日取得。該研究于2020年2月10日發(fā)表于國際優(yōu)異學(xué)術(shù)期刊《癌細(xì)胞》。
研究人員表示，通過響應(yīng)DNA雙鏈斷裂，含MAD2L2的shieldin復(fù)合物在同源重組（HR）和非同源末端連接（NHEJ）兩種修復(fù)方式選擇中起關(guān)鍵作用。
研究人員發(fā)現(xiàn)，EZH2抑制上調(diào)MAD2L2并使擅長HR修復(fù)的上皮性卵巢癌（EOC）對(duì)CARM1依賴性的聚腺苷二磷酸核糖聚合酶（PARP）抑制劑敏感。CARM1通過使MAD2L2啟動(dòng)子上的SWI/SNF復(fù)合物BAF155亞基甲基化來促進(jìn)從SWI/SNF復(fù)合物向EZH2的轉(zhuǎn)換，從而使得MAD2L2沉默。EZH2抑制上調(diào)MAD2L2以減少DNA末端切除，從而增加NHEJ和染色體異常，在PARP抑制劑處理的擅長HR細(xì)胞中引起有絲分裂缺陷。
值得注意的是，在原位和患者來源的荷瘤中，EZH2抑制劑會(huì)使CARM1高表達(dá)的荷瘤對(duì)PPAR抑制劑敏感，但CARM低表達(dá)的則不敏感。
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
Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(19)30585-9
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