Table of primer sequences used for RT-qPCR.

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.

尽管筛查与早期检测已降低了前列腺癌的死亡率，但去势抵抗性疾病（castration-resistant disease, CRPC）仍是不治之症。我们在此报道，联合使用zeste基因增强子同源物2（EZH2）与组蛋白去乙酰化酶（histone deacetylase, HDAC）抑制剂可强效杀灭CRPC细胞，并在侵袭性人类及小鼠CRPC模型中引发显著的肿瘤消退。值得注意的是，EZH2与HDAC均传递转录抑制信号：分别调控组蛋白H3（histone H3）的甲基化与去乙酰化。据此，我们证实，同时抑制EZH2与HDAC，可通过促进组蛋白H3的顺序性去甲基化与乙酰化，解除对一组EZH2靶基因的抑制并诱导其表达。此外，我们发现，其中一个靶基因激活转录因子3（ATF3）——一种广泛的应激反应基因——的诱导，对治疗应答至关重要。重要的是，在人类肿瘤组织中，低水平ATF3表达与患者生存期缩短显著相关。此外，EZH2介导与ATF3介导的转录程序呈负相关，且在晚期疾病中分别呈高、低表达。综上，本研究确定了一种极具前景的CRPC治疗策略，并提示这两种主要表观遗传调控因子可通过缓冲前列腺癌细胞对细胞应激的致死性响应，从而赋予前列腺癌可被靶向干预的治疗脆弱性。