Thyroid hormone receptor beta signaling is a targetable driver of prostate cancer growth
(2025) In Molecular Cancer 24(1).- 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,... (More)
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.
(Less)
- author
- organization
- publishing date
- 2025-12
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Androgen receptor, Murine PCa model, NH-3, Prostate cancer, Thyroid hormone receptor β
- in
- Molecular Cancer
- volume
- 24
- issue
- 1
- article number
- 256
- publisher
- BioMed Central (BMC)
- external identifiers
-
- pmid:41088246
- scopus:105018653603
- ISSN
- 1476-4598
- DOI
- 10.1186/s12943-025-02451-2
- language
- English
- LU publication?
- yes
- id
- 621ea5f0-bf62-4f22-9872-ebd5eef9681e
- date added to LUP
- 2025-12-11 14:35:12
- date last changed
- 2025-12-12 03:00:13
@article{621ea5f0-bf62-4f22-9872-ebd5eef9681e,
abstract = {{<p>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.</p>}},
author = {{Fesiuk, Aleksandra and Pölöske, Daniel and de Araujo, Elvin D. and Frere, Geordon A. and Wright, Timothy B. and Tin, Gary and Raouf, Yasir S. and Olaoye, Olasunkanmi O. and Park, Ji Sung and Blavet, Nicolas and Tichý, Boris and Schlederer, Michaela and Högler, Sandra and Wolf, Michael and Philippe, Cécile and Aksoy, Osman and Varady, Adam and Mata, Alejandro Medaglia and Varenicja, Maxim and Szabó, Boglárka and Weiss, Theresa and Wasinger, Gabriel and Redmer, Torben and Neubauer, Heidi A. and Susani, Martin and Spielvogel, Clemens P. and Ning, Jing and Dahlhoff, Maik and Schepelmann, Martin and Kennedy, Richard and Moriggl, Richard and Brown, Geoffrey and Persson, Jenny and Gerner, Christopher and Bystry, Vojtech and Hollóczki, Oldamur and Heery, David M. and Gunning, Patrick T. and Merkel, Olaf and Hantusch#, Brigitte and Kenner, Lukas}},
issn = {{1476-4598}},
keywords = {{Androgen receptor; Murine PCa model; NH-3; Prostate cancer; Thyroid hormone receptor β}},
language = {{eng}},
number = {{1}},
publisher = {{BioMed Central (BMC)}},
series = {{Molecular Cancer}},
title = {{Thyroid hormone receptor beta signaling is a targetable driver of prostate cancer growth}},
url = {{http://dx.doi.org/10.1186/s12943-025-02451-2}},
doi = {{10.1186/s12943-025-02451-2}},
volume = {{24}},
year = {{2025}},
}