Combating castration-resistant prostate cancer by co-targeting the epigenetic regulators EZH2 and HDAC.
Combating castration-resistant prostate cancer by co-targeting the epigenetic regulators EZH2 and HDAC.
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DOI：
10.1371/journal.pbio.3002038
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发表时间：
2023-04
期刊：
影响因子：
9.8
通讯作者：
中科院分区：
文献类型：
--
作者：
虽然筛查和早期检测降低了前列腺癌的死亡率，但去势抵抗疾病(CRPC)仍然是无法治愈的。在这里，我们报告了EZH2/HDAC联合抑制剂在侵袭性的人类和小鼠CRPC模型中有效地杀死CRPC并导致肿瘤显著消退。值得注意的是，EZH2和HDAC都传递转录抑制信号：分别调节组蛋白H3甲基化和组蛋白去乙酰化。因此，我们表明，通过促进组蛋白H3的顺序去甲基化和乙酰化，抑制EZH2和HDAC是解除/诱导EZH2靶标的子集所必需的。此外，我们发现其中一个靶点ATF3的诱导对治疗反应至关重要，ATF3是一个广泛的应激反应基因。重要的是，在人类肿瘤中，ATF3水平低与生存率下降有关。此外，EZH2和ATF3介导的转录程序呈负相关，在晚期疾病中表达最高/最低。总之，这些研究确定了CRPC的一种有希望的治疗策略，并表明这两种主要的表观遗传调节因子缓冲了前列腺癌对细胞应激的致命反应，从而赋予了一种可处理的治疗脆弱性。表观遗传学、转录和功能研究表明，两种主要的表观遗传学调节因子(EZH2和HDAC)可以缓冲晚期前列腺癌的致死性应激反应，这为去势抵抗疾病提供了一种有前景的联合治疗方法。
While screening and early detection have reduced mortality from prostate cancer, castration-resistant disease (CRPC) is still incurable. Here, we report that combined EZH2/HDAC inhibitors potently kill CRPCs and cause dramatic tumor regression in aggressive human and mouse CRPC models. Notably, EZH2 and HDAC both transmit transcriptional repressive signals: regulating histone H3 methylation and histone deacetylation, respectively. Accordingly, we show that suppression of both EZH2 and HDAC are required to derepress/induce a subset of EZH2 targets, by promoting the sequential demethylation and acetylation of histone H3. Moreover, we find that the induction of one of these targets, ATF3, which is a broad stress response gene, is critical for the therapeutic response. Importantly, in human tumors, low ATF3 levels are associated with decreased survival. Moreover, EZH2- and ATF3-mediated transcriptional programs inversely correlate and are most highly/lowly expressed in advanced disease. Together, these studies identify a promising therapeutic strategy for CRPC and suggest that these two major epigenetic regulators buffer prostate cancers from a lethal response to cellular stresses, thereby conferring a tractable therapeutic vulnerability. Epigenetic, transcriptional, and functional studies show that two major epigenetic regulators (EZH2 and HDAC) buffer advanced prostate cancer from lethal stress responses, revealing a promising combination therapy for castration-resistant disease.
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DOI：
10.1073/pnas.2105898119
发表时间：
2022-01-18
影响因子：
11.1
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
通讯作者：
Xu K
影响因子：
5.4
作者：
Li Y;Seto E
通讯作者：
Seto E
影响因子：
7
作者：
Harrow J;Frankish A;Gonzalez JM;Tapanari E;Diekhans M;Kokocinski F;Aken BL;Barrell D;Zadissa A;Searle S;Barnes I;Bignell A;Boychenko V;Hunt T;Kay M;Mukherjee G;Rajan J;Despacio-Reyes G;Saunders G;Steward C;Harte R;Lin M;Howald C;Tanzer A;Derrien T;Chrast J;Walters N;Balasubramanian S;Pei B;Tress M;Rodriguez JM;Ezkurdia I;van Baren J;Brent M;Haussler D;Kellis M;Valencia A;Reymond A;Gerstein M;Guigó R;Hubbard TJ
通讯作者：
Hubbard TJ
影响因子：
11.5
作者：
Hoy, Sheridan M.
通讯作者：
Hoy, Sheridan M.
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK