CREB5 Promotes Resistance to Androgen-Receptor Antagonists and Androgen Deprivation in Prostate Cancer
CREB5 Promotes Resistance to Androgen-Receptor Antagonists and Androgen Deprivation in Prostate Cancer
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DOI：
10.1016/j.celrep.2019.10.068
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发表时间：
2019-11-19
期刊：
影响因子：
8.8
通讯作者：
Hahn, William C.
中科院分区：
文献类型：
--
作者：
Hwang, Justin H.;Seo, Ji-Heui;Hahn, William C.
雄激素受体（AR）抑制剂（包括Enzalutamide）用于治疗所有转移性去势抵抗性前列腺癌（mCRPC）。然而，有些患者会产生耐药性或从未反应。我们发现转录因子CREB 5在开放阅读框（ORF）表达筛选和肿瘤异种移植物中赋予恩杂鲁胺抗性。CREB 5过表达对于恩杂鲁胺耐药患者来源的类器官是必需的。在表达AR的前列腺癌细胞中，CREB 5相互作用增强Enzalutamide处理后启动子和增强子亚组的AR活性，包括MYC和参与细胞周期的基因。在mCRPC中，我们发现CREB 5的反复扩增和过表达。我们的观察将CREB 5确定为驱动前列腺癌对AR拮抗剂耐药的一种机制。
Androgen-receptor (AR) inhibitors, including enzalutamide, are used for treatment of all metastatic castration-resistant prostate cancers (mCRPCs). However, some patients develop resistance or never respond. We find that the transcription factor CREB5 confers enzalutamide resistance in an open reading frame (ORF) expression screen and in tumor xenografts. CREB5 overexpression is essential for an enzalutamide-resistant patient-derived organoid. In AR-expressing prostate cancer cells, CREB5 interactions enhance AR activity at a subset of promoters and enhancers upon enzalutamide treatment, including MYC and genes involved in the cell cycle. In mCRPC, we found recurrent amplification and overexpression of CREB5. Our observations identify CREB5 as one mechanism that drives resistance to AR antagonists in prostate cancers.