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.
Institute of Biomedicine/Physiology, Biomedicum Helsinki, University of Helsinki, Finland.
Johanna
J
Hirvonen
Ann-Marie
AM
Rajalin
Gerd
G
Wohlfahrt
Herman
H
Adlercreutz
Kristiina
K
Wähälä
Piia
P
Aarnisalo
D000818:Animals; D045744:Cell Line, Tumor; D060754:Equol; D004965:Estrogen Antagonists / Q000494:pharmacology; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology*; D051379:Mice; D048789:Phytoestrogens / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D000097983:ERRalpha Estrogen-Related Receptor
D060754:Equol; D004965:Estrogen Antagonists; D007529:Isoflavones; D048789:Phytoestrogens; D011960:Receptors, Estrogen; D000097983:ERRalpha Estrogen-Related Receptor; C007610:4',7-dihydroxy-3,4-dihydroisoflavone; C098925:Esrrb protein, mouse; C490916:Esrrg protein, mouse