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

Sep 21, 2026

Dysregulated Wnt/β-catenin signaling is common in advanced multiple cancers and is linked to tumor growth, metastasis, and therapy resistance, including prostate cancer and castration-resistant prostate cancer. The transcriptional regulators connecting this pathway to epithelial-mesenchymal transition (EMT) and cancer stemness remain unclear. This study shows NURR1 upregulation in prostate cancer, and demonstrates that NURR1 promotes stemness and EMT in vitro and oncogenic growth in vivo via direct transactivation of CTNNB1 and β-catenin activation, while small molecules modulate NURR1 activity, suggesting therapeutic potential.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages14

Reading Time35 min

AccessFree to download

Introduction

Cancer stem cells and therapy resistance

EMT–stemness linkage in prostate cancer

Wnt/β-catenin signaling in stem cell regulation and cancer

[www.nature.com/cddis](www.nature.com/cddis) ARTICLE OPEN Nuclear receptor NURR1 functions to promote stemness and epithelial-mesenchymal transition in prostate cancer via its targeting of Wnt/β-catenin signaling pathway Xingxing Zhang 1,3, Haolong Li1,2,3, Yuliang Wang 1,3, Hui Zhao 1, Zhu Wang 2 ✉ and Franky Leung Chan 1 ✉ © The Author(s) 2024 | | | | | --- | --- | --- | | | 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 epithelialmesenchymal 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. | | | | Cell Death and Disease (2024)15:234; [https://doi.org/10.1038/s41419-024-06621-w](https://doi.org/10.1038/s41419-024-06621-w) | | | | | | INTRODUCTION A signiﬁcant amount of evidence indicates that a small subset of cancer cells within malignant tumors, designated as cancer stem cells or stem-like cells (CSCs), contribute signiﬁcantly to tumor relapse, metastasis and therapy resistance in advanced cancer development [1, 2] . Prostate cancer stem cells (PCSCs) can be isolated from various preclinical sources and clinical tumor tissues using different methods [3, 4] . Experimental evidence suggests that PCSCs play crucial roles in therapy-resistance, disease relapse, and metastasis [5–7] . During advanced malignant growth, some cancer cells acquire with an embryonic or dedifferentiation cellular process, epithelial-mesenchymal transition (EMT), to enhance their invasion and metastasis capacity. Recent studies show that advanced prostate cancer cells with EMT phenotype exhibit certain cancer stem-like growth features (e.g. enhanced anchorage-independence and tumorigenicity), share common signaling pathways (e.g. Wnt/β-catenin, Notch, hedgehog) and express similar expression patterns (e.g. increased expression of CSC-associated transcription factors and membrane markers)[8–10] . However, the transcriptional control in linking between EMT and cancer stemness in prostate cancer is still not well understood. Wnt/β-catenin signaling is a main signal transduction pathway in the regulation of embryonic development and maintenance of stem cells, and also normal differentiation in adult tissues [11] . It is well characterized that its aberrant expression and mutations of pathway proteins can contribute to the developmen

FAQs

What problem does the study address in prostate cancer progression?

It addresses how Wnt/β-catenin signaling contributes to cancer stemness and EMT during advanced prostate cancer, while noting that the transcriptional regulators involved are not well characterized.

How does NURR1 influence Wnt/β-catenin signaling according to the text?

NURR1 directly transactivates CTNNB1 (β-catenin) and activates β-catenin to drive Wnt/β-catenin signaling, thereby promoting stemness and EMT.

What evidence is provided for NURR1’s role in prostate cancer?

The text reports NURR1 upregulation in prostate cancer and enhanced expression in prostate cancer cell lines, supported by functional and molecular analyses showing effects in vitro and in vivo.

Sep 21, 2026

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