Differential induction of androgen receptor transactivation by different androgen receptor coactivators in human prostate cancer DU145 cells.
Recently identified androgen receptor (AR) coactivators were used in this study to determine whether the specificity of sex hormones and antiandrogens could be modulated at the coactivator level. We found that ARA70 is the best coactivator to confer the androgenic activity on 17beta-estradiol. Only ARA70 and ARA55 could increase significantly the androgenic activity of hydroxyflutamide, a widely used antiand rogen for the treatment of prostate cancer. None of the AR coactivators we tested could significantly confer androgenic activity on progesterone and glucocorticoid at their physiological concentrations (1-10nM). We also found that ARA70, ARA55, and ARA54, but not steroid receptor coactivator-1 (SRC-1) and Rb, could significantly enhance the delta5-androstenediol-mediated AR transactivation. Furthermore, in comparing the relative specificity of these coactivators to AR in DU145 cells, our results suggested that ARA70 has a relatively higher specificity and that SRC-1 can enhance almost equally well many other steroid receptors. Finally, our data demonstrated that AR itself and some select AR coactivators such as ARA70 or ARA54 could, respectively, interact with CBP and p300/CBP-associated factors that have histone acetyl-transferase activity for assisting chromatin remodeling. Together, our data suggest that the specificity of sex hormones and antiandrogens can be modulated by some selective AR coactivators. These findings may not only help us to better understand the specificity of the sex hormones and antiandrogens, but also facilitate the development of better antiandrogens to fight the androgen-related diseases, such as prostate cancer.
Yeh
S
S
Department of Pathology, University of Rochester, NY, USA.
Kang
H Y
HY
Miyamoto
H
H
Nishimura
K
K
Chang
H C
HC
Ting
H J
HJ
Rahman
M
M
Lin
H K
HK
Fujimoto
N
N
Hu
Y C
YC
Mizokami
A
A
Huang
K E
KE
Chang
C
C
D000726:Androgen Antagonists / Q000627:therapeutic use; D002352:Carrier Proteins / Q000494:pharmacology; D005485:Flutamide / Q000031:analogs & derivatives / Q000627:therapeutic use; D012739:Gonadal Steroid Hormones / Q000502:physiology; D051548:Histone Acetyltransferases; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D008297:Male; D056920:Nuclear Receptor Coactivator 1; D056918:Nuclear Receptor Coactivators; D015513:Oncogene Proteins; D011471:Prostatic Neoplasms / Q000188:drug therapy; D011944:Receptors, Androgen / Q000187:drug effects* / Q000502:physiology; D015534:Trans-Activators / Q000494:pharmacology*; D014157:Transcription Factors / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000726:Androgen Antagonists; D002352:Carrier Proteins; D012739:Gonadal Steroid Hormones; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; C111382:NCOA4 protein, human; D056918:Nuclear Receptor Coactivators; D015513:Oncogene Proteins; C118499:RNF14 protein, human; D011944:Receptors, Androgen; C490351:TGFB1I1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; C014290:hydroxyflutamide; D005485:Flutamide; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1