Estrogen-related receptor γ functions as a novel corepressor of androgen receptor by destabilizing receptor conformation and blocking coactivator recruitment

Estrogen-related receptor γ (ERRγ) is an orphan nuclear receptor whose molecular functions in transcriptional regulation remain incompletely understood. The androgen receptor (AR) is a ligand-dependent transcription factor that plays a pivotal role in prostate cancer by regulating gene expression through androgen-response elements. Its activity is tightly controlled by receptor conformation and coactivator recruitment. Although ERRγ has been implicated in the suppression of prostate cancer progression, whether it modulates AR signaling remains unclear. In this study, we examined the functional and molecular interplay between ERRγ and AR using a heterologous expression system in HeLa cells. We found that ERRγ suppresses AR-mediated transcriptional activation in a dose-dependent manner on ARE-containing promoters. Mechanistically, ERRγ interacted with ligand-activated AR in the nucleus and disrupted the intramolecular interaction between the N-terminal domain (NTD) and the C-terminal ligand-binding domain (LBD), which is required for full receptor activation. This interference did not affect AR nuclear translocation. Furthermore, ERRγ functionally competed with major transcriptional coactivators, including steroid receptor coactivators-3 (SRC-3) and p300, thereby attenuating coactivator-enhanced AR-dependent transcription. Collectively, these findings demonstrate that ERRγ functions as a novel corepressor of AR by destabilizing receptor conformation and blocking coactivator recruitment, providing new mechanistic insights into the regulation of AR-mediated transcription.