Dysregulated activation of Wnt/β-catenin signaling pathway is a frequent or common event during advanced progression of multiple cancers. With this signaling activation, it enhances their tumorigenic growth and facilitates metastasis and therapy resistance. Advances show that this signaling pathway can play dual regulatory roles in the control of cellular processes epithelial-mesenchymal transition (EMT) and cancer stemness in cancer progression. Aberrant activation of Wnt/β-catenin signaling pathway is shown to be common in prostate cancer and also castration-resistant prostate cancer (CRPC). However, the transcriptional regulators of this pathway in prostate cancer are still not well characterized. NURR1 (NR4A2) is an orphan nuclear receptor and plays an important role in the development of dopaminergic neurons. Previously, we have shown that NURR1 exhibits an upregulation in isolated prostate cancer stem-like cells (PCSCs) and a xenograft model of CRPC. In this study, we further confirmed that NURR1 exhibited an upregulation in prostate cancer and also enhanced expression in prostate cancer cell lines. Functional and molecular analyses showed that NURR1 could act to promote both in vitro (cancer stemness and EMT) and also in vivo oncogenic growth of prostate cancer cells (metastasis and castration resistance) via its direct transactivation of CTNNB1 (β-catenin) and activation of β-catenin to mediate the activation of Wnt/β-catenin signaling pathway. Moreover, we also demonstrated that NURR1 activity in prostate cancer cells could be modulated by small molecules, implicating that NURR1 could be a potential therapeutic target for advanced prostate cancer management.

Wnt/β-连环蛋白信号通路的激活失调是多种癌症晚期进展过程中的常见事件。通过这种信号激活，它增强了它们的致瘤性生长并促进了转移和治疗耐药性。研究进展表明，该信号通路可以在控制细胞过程上皮间质转化（EMT）和癌症进展中的癌症干性中发挥双重调节作用。 Wnt/β-连环蛋白信号通路的异常激活在前列腺癌和去势抵抗性前列腺癌 (CRPC) 中很常见。然而，前列腺癌中该途径的转录调节因子仍未得到很好的表征。 NURR1 ( NR4A2 ) 是一种孤儿核受体，在多巴胺能神经元的发育中发挥重要作用。此前，我们已经证明 NURR1 在分离的前列腺癌干样细胞 (PCSC) 和 CRPC 异种移植模型中表现出上调。在这项研究中，我们进一步证实 NURR1 在前列腺癌中表现出上调，并且在前列腺癌细胞系中表达也增强。功能和分子分析表明，NURR1 可以通过 CTNNB1（β-连环蛋白）的直接反式激活和β-catenin 介导 Wnt/β-catenin 信号通路的激活。此外，我们还证明前列腺癌细胞中的 NURR1 活性可以通过小分子调节，这意味着 NURR1 可能是晚期前列腺癌管理的潜在治疗靶点。