Neuroendocrine prostate cancer (NEPC) is an aggressive malignancy with no effective targeted therapies. The oncogenic MUC1-C protein is overexpressed in castration-resistant prostate cancer (CRPC) and NEPC, but its specific role is unknown. Here, we demonstrate that upregulation of MUC1-C in androgen-dependent PC cells suppresses androgen receptor (AR) axis signaling and induces the neural BRN2 transcription factor. MUC1-C activates a MYC→BRN2 pathway in association with induction of MYCN, EZH2 and NE differentiation markers (ASCL1, AURKA and SYP) linked to NEPC progression. Moreover, MUC1-C suppresses the p53 pathway, induces the Yamanaka pluripotency factors (OCT4, SOX2, KLF4 and MYC) and drives stemness. Targeting MUC1-C decreases PC self-renewal capacity and tumorigenicity, suggesting a potential therapeutic approach for CRPC and NEPC. In PC tissues, MUC1 expression associates with suppression of AR signaling and increases in BRN2 expression and NEPC score. These results highlight MUC1-C as a master effector of lineage plasticity driving progression to NEPC.

神经内分泌前列腺癌（NEPC）是一种恶性肿瘤，没有有效的靶向治疗方法。致癌性MUC1-C蛋白在去势抵抗性前列腺癌（CRPC）和NEPC中过表达，但其具体作用尚不清楚。在这里，我们证明了雄激素依赖性PC细胞中MUC1-C的上调抑制了雄激素受体（AR）轴信号传导并诱导了神经BRN2转录因子。MUC1-C激活MYC→BRN2途径，并诱导与NEPC进展相关的MYCN，EZH2和NE分化标志物（ASCL1，AURKA和SYP）。此外，MUC1-C抑制p53途径，诱导Yamanaka多能性因子（OCT4，SOX2，KLF4和MYC）并驱动茎干。靶向MUC1-C降低了PC的自我更新能力和致瘤性，提示了CRPC和NEPC的潜在治疗方法。在PC组织中，MUC1的表达与AR信号的抑制有关，并增加BRN2的表达和NEPC评分。这些结果突出表明MUC1-C是谱系可塑性的主要效应物，推动了向NEPC的发展。