Emergence of an aggressive androgen receptor (AR)-independent neuroendocrine prostate cancer (NEPC) after androgen-deprivation therapy (ADT) is well-known. Nevertheless, the majority of advanced-stage prostate cancer patients, including those with SPINK1-positive subtype, are treated with AR-antagonists. Here, we show AR and its corepressor, REST, function as transcriptional-repressors of SPINK1, and AR-antagonists alleviate this repression leading to SPINK1 upregulation. Increased SOX2 expression during NE-transdifferentiation transactivates SPINK1, a critical-player for maintenance of NE-phenotype. SPINK1 elicits epithelial-mesenchymal-transition, stemness and cellular-plasticity. Conversely, pharmacological Casein Kinase-1 inhibition stabilizes REST, which in cooperation with AR causes SPINK1 transcriptional-repression and impedes SPINK1-mediated oncogenesis. Elevated levels of SPINK1 and NEPC markers are observed in the tumors of AR-antagonists treated mice, and in a subset of NEPC patients, implicating a plausible role of SPINK1 in treatment-related NEPC. Collectively, our findings provide an explanation for the paradoxical clinical-outcomes after ADT, possibly due to SPINK1 upregulation, and offers a strategy for adjuvant therapies.

中文翻译：

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雄激素剥夺上调SPINK1表达并增强前列腺癌中的细胞可塑性。

雄激素剥夺治疗（ADT）后，侵略性雄激素受体（AR）独立的神经内分泌前列腺癌（NEPC）的出现是众所周知的。尽管如此，大多数晚期前列腺癌患者，包括那些具有SPINK1阳性亚型的患者，都接受了AR拮抗剂治疗。在这里，我们显示AR及其共抑制因子REST作为SPINK1的转录抑制因子起作用，而AR拮抗剂可减轻这种抑制作用，从而导致SPINK1上调。NE转分化过程中增加的SOX2表达可激活SPINK1，SPINK1是维持NE表型的关键因素。SPINK1引起上皮-间质转化，干性和细胞可塑性。相反，药理酪蛋白激酶1抑制作用可稳定REST，与AR协同作用会导致SPINK1转录抑制并阻碍SPINK1介导的肿瘤发生。在接受AR拮抗剂治疗的小鼠和部分NEPC患者的肿瘤中观察到SPINK1和NEPC标记水平升高，这暗示了SPINK1在与治疗相关的NEPC中的合理作用。总的来说，我们的发现为ADT可能由SPINK1上调引起的自相矛盾的临床结果提供了解释，并提供了辅助治疗的策略。