Transcriptional activity of estrogen-related receptor gamma (ERR gamma) is stimulated by the phytoestrogen equol

Estrogen-related receptor gamma (ERR gamma) is an orphan nuclear receptor lacking identified natural ligands. The synthetic estrogen receptor ligands 4-hydroxytamoxifen and diethylstilbestrol have, however, been shown to bind to and abolish the constitutive transcriptional activity of ERR gamma. Certain phytoestrogens were recently reported to act as agonists of the related ERR alpha. We investigated whether phytoestrogens also modulated the transcriptional activity of ERR gamma. We analyzed a selection of phytoestrogens for their potential agonistic or antagonistic activity on ERR gamma. In transiently transfected PC-3 and U2-OS cells equol stimulated the transcriptional activity of ERR gamma and enhanced its interaction with the coactivator GRIP1. The agonistic effect of equol was abolished by 4-hydroxytamoxifen. Equol induced a conformational change in the ERR gamma ligand-binding domain. Based on structural models of the ERR gamma ligand-binding domain, we were able to introduce mutations that modulated the agonistic potential of equol. Finally, equol enhanced the growth inhibitory effect of ERR gamma on the prostate cancer PC-3 cells. In conclusion, we have demonstrated that the phytoestrogen equol acts as an ERR gamma agonist. (C) 2010 Elsevier Ltd. All rights reserved.