Inhibition of EZH2 transactivation function sensitizes solid tumors to genotoxic stress.
Inhibition of EZH2 transactivation function sensitizes solid tumors to genotoxic stress.
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EZH2反式激活功能的抑制使实体瘤对遗传毒性应激敏感。
DOI：
10.1073/pnas.2105898119
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发表时间：
2022-01-18
影响因子：
11.1
通讯作者：
Xu K
中科院分区：
文献类型：
--
作者：
Liao Y;Chen CH;Xiao T;de la Peña Avalos B;Dray EV;Cai C;Gao S;Shah N;Zhang Z;Feit A;Xue P;Liu Z;Yang M;Lee JH;Xu H;Li W;Mei S;Pierre RS;Shu S;Fei T;Duarte M;Zhao J;Bradner JE;Polyak K;Kantoff PW;Long H;Balk SP;Liu XS;Brown M;Xu K
我们鉴定了一组由EZH 2直接诱导并被EZH 2抑制剂抑制的DNA修复基因。这些基因的表达可预测携带野生型EZH 2的实体瘤对EZH 2抑制剂的反应。最重要的是，我们的研究结果为开发EZH 2抑制剂和DNA损伤剂或阻断DNA修复的药物联合治疗去势抵抗性前列腺癌和其他实体瘤奠定了基础。阻断甲基转移酶EZH 2活性的药物正在临床开发中，用于治疗携带EZH 2功能获得性突变的非霍奇金淋巴瘤，EZH 2功能获得性突变增强了其多梳抑制功能。我们以前曾报道EZH 2可以作为去势抵抗性前列腺癌（CRPC）的转录激活因子。现在我们发现EZH 2抑制剂也可以阻断EZH 2的反式激活活性并抑制CRPC细胞的生长。用EZH 2抑制剂处理的细胞的基因表达和表观基因组学分析表明，除了去抑制基因表达外，这些化合物还稳健地下调一组DNA损伤修复（DDR）基因，特别是参与碱基切除修复（BER）途径的那些基因。EZH 2对先驱因子FOXA 1的甲基化有助于这些基因的激活，并且通过EZH 2上的反式激活结构域与转录辅激活因子P300的相互作用直接开启转录。此外，在存在EZH 2抑制剂的情况下，CRISPR-Cas9介导的敲除筛选将这些BER基因鉴定为EZH 2抑制剂的生长抑制作用的决定因素。对来自表达野生型EZH 2的不同类型实体瘤的公开数据的询问表明，DDR基因的表达与EZH 2依赖性和细胞对EZH 2抑制剂的敏感性显著相关。与这些发现一致，用EZH 2抑制剂处理CRPC细胞显著增强了其对遗传毒性应激的敏感性。这些研究揭示了EZH 2抑制剂以前未被认识到的作用机制，并为潜在的联合癌症治疗提供了机制基础。
We identified a group of DNA repair genes directly induced by EZH2 and repressed by EZH2 inhibitors. Expression of these genes predicts the response of wild-type EZH2-harboring solid tumors to EZH2 inhibitors. Most importantly, our findings lay the foundation for the development of a combination therapy that combines EZH2 inhibitors and DNA damaging agents or drugs that block DNA repair for the treatment of castration-resistant prostate cancer and other solid tumors. Drugs that block the activity of the methyltransferase EZH2 are in clinical development for the treatment of non-Hodgkin lymphomas harboring EZH2 gain-of-function mutations that enhance its polycomb repressive function. We have previously reported that EZH2 can act as a transcriptional activator in castration-resistant prostate cancer (CRPC). Now we show that EZH2 inhibitors can also block the transactivation activity of EZH2 and inhibit the growth of CRPC cells. Gene expression and epigenomics profiling of cells treated with EZH2 inhibitors demonstrated that in addition to derepressing gene expression, these compounds also robustly down-regulate a set of DNA damage repair (DDR) genes, especially those involved in the base excision repair (BER) pathway. Methylation of the pioneer factor FOXA1 by EZH2 contributes to the activation of these genes, and interaction with the transcriptional coactivator P300 via the transactivation domain on EZH2 directly turns on the transcription. In addition, CRISPR-Cas9–mediated knockout screens in the presence of EZH2 inhibitors identified these BER genes as the determinants that underlie the growth-inhibitory effect of EZH2 inhibitors. Interrogation of public data from diverse types of solid tumors expressing wild-type EZH2 demonstrated that expression of DDR genes is significantly correlated with EZH2 dependency and cellular sensitivity to EZH2 inhibitors. Consistent with these findings, treatment of CRPC cells with EZH2 inhibitors dramatically enhances their sensitivity to genotoxic stress. These studies reveal a previously unappreciated mechanism of action of EZH2 inhibitors and provide a mechanistic basis for potential combination cancer therapies.
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DOI：
10.1073/pnas.1703966114
发表时间：
2017-11-14
影响因子：
11.1
作者：
Januario, Thomas;Ye, Xiaofen;Yauch, Robert L.
通讯作者：
Yauch, Robert L.
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
16.6
作者：
Huether, Robert;Dong, Li;Chen, Xiang;Wu, Gang;Parker, Matthew;Wei, Lei;Ma, Jing;Edmonson, Michael N.;Hedlund, Erin K.;Rusch, Michael C.;Shurtleff, Sheila A.;Mulder, Heather L.;Boggs, Kristy;Vadordaria, Bhavin;Cheng, Jinjun;Yergeau, Donald;Song, Guangchun;Becksfort, Jared;Lemmon, Gordon;Weber, Catherine;Cai, Zhongling;Dang, Jinjun;Walsh, Michael;Gedman, Amanda L.;Faber, Zachary;Easton, John;Gruber, Tanja;Kriwacki, Richard W.;Partridge, Janet F.;Ding, Li;Wilson, Richard K.;Mardis, Elaine R.;Mullighan, Charles G.;Gilbertson, Richard J.;Baker, Suzanne J.;Zambetti, Gerard;Ellison, David W.;Zhang, Jinghui;Downing, James R.
通讯作者：
Downing, James R.
DOI：
10.1073/pnas.1914866117
发表时间：
2020-07-21
影响因子：
11.1
作者：
Jiao, Lianying;Shubbar, Murtada;Liu, Xin
通讯作者：
Liu, Xin
DOI：
10.1073/pnas.1002175107
发表时间：
2010-04-13
影响因子：
11.1
作者：
de Feraudy, Sebastien;Revet, Ingrid;Cleaver, James E.
通讯作者：
Cleaver, James E.