EZH2抑制使CARM1高表達卵巢癌對PARP抑制敏感
作者:
小柯機器人發布時間:2020/2/29 23:36:54
EZH2抑制能夠使CARM1高表達且擅長同源重組修復的卵巢癌對PARP抑制敏感,這一成果由美國威斯塔研究所Rugang Zhang團隊近日取得。該研究於2020年2月10日發表於國際一流學術期刊《癌細胞》。
研究人員表示,通過響應DNA雙鏈斷裂,含MAD2L2的shieldin複合物在同源重組(HR)和非同源末端連接(NHEJ)兩種修複方式選擇中起關鍵作用。
研究人員發現,EZH2抑制上調MAD2L2並使擅長HR修復的上皮性卵巢癌(EOC)對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啟動子上的SWI/SNF複合物BAF155亞基甲基化來促進從SWI/SNF複合物向EZH2的轉換,從而使得MAD2L2沉默。EZH2抑制上調MAD2L2以減少DNA末端切除,從而增加NHEJ和染色體異常,最終在PARP抑制劑處理的擅長HR細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抑制劑會使CARM1高表達的荷瘤對PPAR抑制劑敏感,但CARM低表達的則不敏感。
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