Thyroid hormone receptor beta signaling is a targetable driver of prostate cancer growth

Title (eng)
Thyroid hormone receptor beta signaling is a targetable driver of prostate cancer growth
Author
Aleksandra Fesiuk
Author
Daniel Pölöske
Author
Elvin D. de Araujo
Author
Geordon A. Frere
Author
Timothy B. Wright
Author
Gary Tin
Author
Yasir S. Raouf
Author
Olasunkanmi O. Olaoye
Author
Ji Sung Park
Author
Nicolas Blavet
Author
Boris Tichý
Author
Michaela Schlederer
Author
Sandra Högler
Author
Michael Wolf
Author
Cécile Philippe
Author
Osman Aksoy
Author
Adam Varady
Author
Alejandro Medaglia Mata
Author
Maxim Varenicja
Author
Boglárka Szabó
Author
Theresa Weiss
Author
Gabriel Wasinger
Author
Torben Redmer
Author
Heidi A. Neubauer
Author
Martin Susani
Author
Clemens P. Spielvogel
Author
Jing Ning
Author
Maik Dahlhoff
Author
Martin Schepelmann
Author
Richard Kennedy
Author
Richard Moriggl
Author
Geoffrey Brown
Author
Jenny Persson
Author
Christopher Gerner
Author
Vojtech Bystry
Author
Oldamur Hollóczki
Author
David M. Heery
Author
Patrick T. Gunning
Author
Olaf Merkel
Author
Brigitte Hantusch
Author
Lukas Kenner
Author
Aleksandra Fesiuk
Abstract (eng)
Thyroid hormone (TH) signaling plays a major role in the development, energy homeostasis, and metabolism of most tissues. Recent studies have identified THs as drivers of prostate cancer (PCa) development and progression. We reported that the T3-scavenger protein µ-crystallin (CRYM) regulates the development and progression of PCa and that this involved crosstalk with androgen receptor (AR) signaling. However, the mechanisms remain incompletely understood. Here, we explored the role of thyroid hormone receptor β (TRβ), which is the main effector of TH signaling, in the context of PCa. The use of the TRβ-selective antagonist NH-3 inhibited PCa cell proliferation in vitro and reduced tumor size in PCa xenograft models in vivo. Notably, NH-3 was highly effective in the engrafted 22Rv1 cell line, a model for castration-resistant PCa (CRPC). Mechanistic studies revealed that NH-3 downregulates AR and the AR target genes Nkx3.1 and KLK3 (PSA). NH-3 was a more effective anticancer agent than enzalutamide, and their combined use was synergistic. Evidence from human datasets corroborates our findings, whereby elevated TRβ expression and mutations in the TH signaling pathway are associated with the onset of PCa. Collectively, these results establish TRβ as a mediator of tumorigenesis in PCa and identify NH-3 as a promising therapeutic agent for targeting AR signaling, particularly in CRPC.
Keywords (eng)
Thyroid Hormone Receptor βProstate CancerNH-3Androgen ReceptorMurine PCa Model
Type (eng)
journal article
Language
[eng]
Persistent identifier
https://phaidra.vetmeduni.ac.at/o:5028
DOI
10.1186/s12943-025-02451-2
Is in series
Title (eng)
Molecular Cancer
Volume
24
Issue
1
ISSN
1476-4598
Issued
2025
Number of pages
21
Publication
Springer
Version type (eng)
version of record (published version)
Date issued
2025
Access rights (eng)
open access
License
CC BY 4.0 International
Rights statement (eng)
© 2025, The Author(s)