Transcriptional activity of estrogen-related receptor γ (ERRγ) is stimulated by the phytoestrogen equol

Estrogen-related receptor γ (ERRγ) 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 ERRγ. Certain phytoestrogens were recently reported to act as agonists of the related ERRα. We investigated whether phytoestrogens also modulated the transcriptional activity of ERRγ. We analyzed a selection of phytoestrogens for their potential agonistic or antagonistic activity on ERRγ. In transiently transfected PC-3 and U2-OS cells equol stimulated the transcriptional activity of ERRγ 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 ERRγ ligand-binding domain. Based on structural models of the ERRγ ligand-binding domain, we were able to introduce mutations that modulated the agonistic potential of equol. Finally, equol enhanced the growth inhibitory effect of ERRγ on the prostate cancer PC-3 cells. In conclusion, we have demonstrated that the phytoestrogen equol acts as an ERRγ agonist.

Research highlights▶ The phytoestrogen equol acts as an ERRγ agonist. ▶ The agonistic effect of equol on ERRγ is abolished by 4-hydroxytamoxifen ▶ Equol enhances the interaction between ERRγ and the transcriptional coactivator GRIP1. ▶ Equol induces a conformational change in the ERRγ ligand-binding domain ▶ Equol enhances the growth inhibitory effect of ERRγ on the prostate cancer PC-3 cells.