Nuclear receptor TLX functions to promote cancer stemness and EMT in prostate cancer via its direct transactivation of CD44 and stem cell-regulatory transcription factors.

Autor: Chow ST; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong, China., Fan J; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong, China., Zhang X; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong, China., Wang Y; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong, China., Li Y; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong, China., Ng CF; Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong, China., Pei X; Department of Pathology, Shenzhen Hospital, Southern Medical University, Shenzhen, Guandong, China., Zheng Q; Department of Urology, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong Province, China., Wang F; Department of Urology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province, China., Wu D; Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong, China. wudinglan@163.com.; Department of Urology and The Clinical Innovation & Research Center (CIRC), Shenzhen Hospital, Southern Medical University, Shenzhen, China. wudinglan@163.com., Chan FL; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong, China. franky-chan@cuhk.edu.hk.
Jazyk: angličtina
Zdroj: British journal of cancer [Br J Cancer] 2024 Nov; Vol. 131 (9), pp. 1450-1462. Date of Electronic Publication: 2024 Sep 26.
DOI: 10.1038/s41416-024-02843-z
Abstrakt: Background: Prostate cancer stem cells (PCSCs) play crucial roles in therapy-resistance and metastasis in castration-resistant prostate cancer (CRPC). Certain functional link between cancer stemness and epithelial-mesenchymal transition (EMT) is involved in CRPC. However, up-stream regulators controlling these two processes in PCSCs are still poorly understood. Recently, we have shown that orphan nuclear receptor TLX can promote tumour initiation and progression in CRPC by repressing androgen receptor and oncogene-induced senescence.
Methods: PCSCs were isolated from various prostate cancer cell lines and clinical tumour tissues using multiple methods for various in vitro and in vivo oncogenic growth analyses. Direct targets of TLX involved in stemness and EMT regulation were determined by specific reporter gene assays and ligand-driven modulation of TLX activity.
Results: PCSCs isolated from various sources exhibited increased expression of TLX. Functional and molecular characterisation showed that TLX could function to promote cancer stemness and EMT in prostate cancer cells via its direct transactivation of CD44, SOX2, POU5F1 and NANOG, which share certain functional crosstalk in these two cellular processes.
Conclusions: TLX could act as a key up-stream regulator in transcriptional control of stemness and EMT in PCSCs, which contribute to their tumorigenicity, castration-resistance and metastasis potentials in advanced prostate cancer.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
Externí odkaz: