尽管最初有效，但长期雄激素剥夺疗法（ADT）会促进神经内分泌分化（NED）和前列腺癌（PCa）进展。 ADT 如何在 PCa 细胞中转录诱导 NE 基因尚不完全清楚。已知 CREB1 和 REST 分别对大脑中的神经元基因表达进行正向和负向调节。 PCa 的 NED 中尚未阐明这两个主要神经元调节因子之间的直接联系。我们发现 REST mRNA 在 NEPC 细胞和小鼠模型以及患者样本中下调。从表型上看，REST 过表达会增加 ADT 敏感性、抑制 NE 基因、抑制培养物中的集落形成以及 PCa 细胞的异种移植肿瘤生长。正如预期的那样，ADT 下调培养的 PCa 细胞和小鼠异种移植物中的 REST。有趣的是，CREB1 信号传导抑制 REST 表达。在研究 ADT 对 REST 转录抑制的机制尚不清楚时，我们发现 REST 是 EZH2 表观遗传抑制的直接目标。最后，基因拯救实验表明，ADT 通过 EZH2 对 REST 的抑制来诱导 NED，而 ADT 激活的 CREB1 信号传导会增强这种抑制。总之，我们的研究揭示了 ADT 上调 NE 基因的关键途径，并在 CREB1 和 REST 之间以及 EZH2 和 REST 之间建立了新的关系，这也可能对其他癌症类型和神经生物学产生影响。© 2024。这是美国政府作品，在美国不受版权保护；可能适用外国版权保护。

Although effective initially, prolonged androgen deprivation therapy (ADT) promotes neuroendocrine differentiation (NED) and prostate cancer (PCa) progression. It is incompletely understood how ADT transcriptionally induces NE genes in PCa cells. CREB1 and REST are known to positively and negatively regulate neuronal gene expression in the brain, respectively. No direct link between these two master neuronal regulators has been elucidated in the NED of PCa. We show that REST mRNA is downregulated in NEPC cell and mouse models, as well as in patient samples. Phenotypically, REST overexpression increases ADT sensitivity, represses NE genes, inhibits colony formation in culture, and xenograft tumor growth of PCa cells. As expected, ADT downregulates REST in PCa cells in culture and in mouse xenografts. Interestingly, CREB1 signaling represses REST expression. In studying the largely unclear mechanism underlying transcriptional repression of REST by ADT, we found that REST is a direct target of EZH2 epigenetic repression. Finally, genetic rescue experiments demonstrated that ADT induces NED through EZH2's repression of REST, which is enhanced by ADT-activated CREB1 signaling. In summary, our study has revealed a key pathway underlying NE gene upregulation by ADT, as well as established novel relationships between CREB1 and REST, and between EZH2 and REST, which may also have implications in other cancer types and in neurobiology.© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.