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

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.

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Publication Details

Journal
Molecular Cancer
Published
2025-10-14
DOI
https://doi.org/10.1186/s12943-025-02451-2
Primary Topic
Prostate Cancer Treatment and Research
Type
article
Field-Weighted Citation Impact
0.00

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

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

Adam Varady, Clemens P. Spielvogel, Elvin D. de Araujo, Heidi A. Neubauer, Gabriel Wasinger, Vojtěch Bystrý, Geordon A. Frere, Martin Susani, Yasir S. Raouf, Richard Moriggl, Aleksandra Fesiuk, Gary Tin, Theresa R. Weiss, Maik Dahlhoff, Boglárka Szabó, Michaela Schlederer, Nicolas Blavet, Christopher Gerner, Patrick Thomas Gunning, Ji Sung Park, Torben Redmer, Oldamur Hollóczki, Olasunkanmi O. Olaoye, Sandra Högler, Osman Aksoy, Lukas Kenner, Olaf Merkel, Daniel Pölöske, Timothy Wright, G. E. Brown, Jenny Persson, Boris Tichý, Martin Schepelmann, Brigitte Hantusch, Cécile Philippe, David M. Heery, Jing Ning, Richard Kennedy, Alejandro Medaglia Mata, Michael Wolf, Maxim Varenicja
article en

Abstract

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.

Molecular CancerVol. 24(1)
University of Vienna (AT), Central European Institute of Technology (CZ), University of Debrecen (HU), University of Nottingham (GB), University of Veterinary Medicine Vienna (AT), University of Salzburg (AT), University of Toronto (CA), Lund University (SE), College of Family Physicians of Canada (CA), Central European Institute of Technology – Masaryk University (CZ), Comprehensive Cancer Center Vienna (AT), Christian Doppler Laboratory for Thermoelectricity (AT), St Anna Children's Hospital (AT), The Northern Ireland Cancer Centre (GB), Center For Biomarker Research In Medicine (AT), Almac (United Kingdom) (GB), Community Research Initiative (US), Karl Landsteiner University of Health Sciences (AT), Karl Landsteiner Society (AT), St. Anna Children's Cancer Research Institute, Medical University of Vienna (AT), University of Birmingham (GB), Umeå University (SE)
Österreichische Nationalstiftung für Forschung, Technologie und Entwicklung, European Commission, Vienna Science and Technology Fund, Ministerstvo Školství, Mládeže a Tělovýchovy, Austrian Science Fund, Universität Wien, Bundesministerium für Wissenschaft, Forschung und Wirtschaft, Hungarian Scientific Research Fund, Magyar Tudományos Akadémia, Österreichische Forschungsförderungsgesellschaft, Medizinische Universität Wien, Christian Doppler Forschungsgesellschaft, Siemens Healthineers, Bundesministerium für Digitalisierung und Wirtschaftsstandort, Nemzeti Kutatási, Fejlesztési és Innovaciós Alap, National Research, Development and Innovation Office
Openalex Percentile: Top 58%
Prostate Cancer Treatment and Research
DOIOpen Access PDFOpenAlex
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