Nuclear receptor NURR1 functions to promote stemness and epithelial-mesenchymal transition in prostate cancer via its targeting of Wnt/β-catenin signaling pathway

作者：Xingxing Zhang, Haolong Li, Yuliang Wang, Hui Zhao, Zhu Wang, Franky Leung Chan · 发表于：Cell Death and Disease · 年份：2024 · DOI：10.1038/s41419-024-06621-w · 被引用次数：20 · 研究领域：Nuclear Receptors and Signaling、Circular RNAs in diseases、Macrophage Migration Inhibitory Factor

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 demon...