The androgen receptor recruits nuclear receptor CoRepressor (N-CoR) in the presence of mifepristone via its N and C termini revealing a novel molecular mechanism for androgen receptor antagonists.
The androgen receptor (AR) activates target gene expression in the presence of agonist ligands via the recruitment of transcriptional coactivators, but recent work shows that overexpression of the nuclear corepressors NCoR and SMRT attenuates this agonist-mediated AR activation. Here we demonstrate using NCoR siRNA and chromatin immunoprecipitation that endogenous NCoR is recruited to and represses the dihydrotestosterone (DHT)-liganded AR. Furthermore this study shows that NCoR and coactivators compete for AR in the presence of DHT. AR antagonists such as bicalutamide that are currently in use for prostate cancer treatment can also mediate NCoR recruitment, but mifepristone (RU486) at nanomolar concentrations is unique in its ability to markedly enhance the AR-NCoR interaction. The RU486-liganded AR interacted with a C-terminal fragment of NCoR, and this interaction was mediated by the two most C-terminal nuclear receptor interacting domains (RIDs) present in NCoR. Significantly, in addition to the AR ligand binding domain, the AR N terminus was also required for this interaction. Mutagenesis studies demonstrate that the N-terminal surface of the AR-mediating NCoR recruitment was distinct from tau5 and from the FXXLF motif that mediates agonist-induced N-C-terminal interaction. Taken together these data demonstrate that NCoR is a physiological regulator of the AR and reveal a new mechanism for AR antagonism that may be exploited for the development of more potent AR antagonists.
Hodgson
Myles C
MC
Division of Hematology/Oncology and Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
Astapova
Inna
I
Cheng
Shinta
S
Lee
Larissa J
LJ
Verhoeven
Manon C
MC
Choi
Eunis
E
Balk
Steven P
SP
Hollenberg
Anthony N
AN
D059002:Androgen Receptor Antagonists; D001665:Binding Sites; D001667:Binding, Competitive; D002460:Cell Line; D045744:Cell Line, Tumor; D013196:Dihydrotestosterone / Q000378:metabolism; D006727:Hormone Antagonists / Q000494:pharmacology*; D006801:Humans; D015735:Mifepristone / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000378:metabolism* / Q000502:physiology; D056971:Nuclear Receptor Co-Repressor 1; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000187:drug effects; D011944:Receptors, Androgen / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism* / Q000502:physiology; D014162:Transfection
D059002:Androgen Receptor Antagonists; D006727:Hormone Antagonists; C539127:NCOR1 protein, human; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D011944:Receptors, Androgen; D012097:Repressor Proteins; D013196:Dihydrotestosterone; D015735:Mifepristone