Differential modulation of androgen receptor transcriptional activity by the nuclear receptor co-repressor (N-CoR)

Abstract

Antiandrogens are widely used agents in the treatment of prostate cancer, as inhibitors of AR (androgen receptor) action. Although the precise mechanism of antiandrogen action is not yet elucidated, recent studies indicate the involvement of nuclear receptor co-repressors. In the present study, the regulation of AR transcriptional activity by N-CoR (nuclear receptor co-repressor), in the presence of different ligands, has been investigated. Increasing levels of N-CoR differentially affected the transcriptional activity of AR occupied with either agonistic or antagonistic ligands. Small amounts of co-transfected N-CoR repressed CPA (cyproterone acetate)-and mifepristone (RU486)-mediated AR activity, but did not affect agonist (R1881)-induced AR activity. Larger amounts of co-transfected N-CoR repressed AR activity for all ligands, and converted the partial agonists CPA and RU486 into strong AR antagonists. In the presence of the agonist R1881, co-expression of the p160 co-activator TIF2 (transcriptional intermediary factor 2) relieved N-CoR repression up to control levels. However, in the presence of RU486 and CPA, TIF2 did not functionally compete with N-CoR, suggesting that antagonistbound AR has a preference for N-CoR. The AR mutation T877A (Thr 877 → Ala), which is frequently found in prostate cancer and affects the ligand-induced conformational change of the AR, considerably reduced the repressive action of NCoR. The agonistic activities of CPA-and hydroxyflutamideoccupied T877A-AR were hardly affected by N-CoR, whereas TIF2 strongly enhanced their activities. These results indicate that lack of N-CoR action allows these antiandrogens to act as strong agonists on the mutant AR.

Ligand-Specific Dynamics of the Androgen Receptor at Its Response Element in Living Cells

“…Upon binding to DNA, sequences found in the NTD (called activation function 1 ) and LBD (AF-2) facilitate activation of transcription. Genetic and biochemical experiments have indicated that the LBD of AR interacts with the NTD upon ligand binding (7,14,27,32,82), which is similar to the results observed for the ER (39). This intramolecular interaction has been shown to be important for optimal receptor activity (7,12,14,32,82).…”

Imaging androgen receptor function during flutamide treatment in the LAPC9 xenograft model

“…In contrast, we find little polymerase II bound to the promoter in the presence of flutamide. This observation in the tumor is consistent with cell culture studies showing that Casodex may actively repress the PSA gene by permitting androgen receptor to interact with corepressors (32,43,44). In addition, flutamide decreases the association of androgen receptor with various coactivators including TIF2, which in turn affects androgen receptor -mediated transcriptional activity (43,45).…”

DJ-1 Binds Androgen Receptor Directly and Mediates Its Activity in Hormonally Treated Prostate Cancer Cells

“…Additionally, DHT and bicalutamide treatment resulted in DJ-1-AR colocalization throughout the nucleus, whereas DJ-1-AR seemed to concentrate just inside the nuclear perimeter after OH-flutamide treatment. These differences may be due to the well-characterized AR T877A substitution mutation in LNCaP cells (32)(33)(34). This mutation allows flutamide to exhibit agonist activity; however, because this mutation causes an AR conformational change, it could inhibit the interaction with DJ-1.…”