Thyroid Hormone Receptor Beta Signaling is a Targetable Driver of Prostate Cancer Growth

ABSTRACT Thyroid hormone (TH) signaling plays a major role in the development, energy homeostasis, and metabolism of most tissues. Recent observations have identified THs as drivers of prostate cancer (PCa) tumor 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 the 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. 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 showed synergistic properties in combined use. Evidence from human datasets corroborates our findings whereby elevated TRβ expression and mutations in TH signaling pathways 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.