Expression and function of androgen receptor coactivators in prostate cancer.
Human androgen receptor (AR) associates with coactivator or corepressor proteins that modulate its activation in the presence of ligand. Early studies on AR coactivators in carcinoma of the prostate were hampered because of lack of respective antibodies. Investigations at mRNA level revealed that most benign and malignant prostate cells express common coactivators. AR coactivators SRC-1 and TIF-2 are up-regulated in tissue specimens obtained from patients who failed prostate cancer endocrine therapy. Increased expression of these coactivators is associated with enhanced activation of the AR by the adrenal androgen dehydroepiandrosterone. Similar association between AR coactivator expression and high prostate cancer grade and stage was reported for RAC-3 (SRC-3). The transcriptional integrator CBP was detected in clinical specimens representing organ-confined prostate cancer, lymph node metastases and tumour cell lines. Agonistic effect of the nonsteroidal antiandrogen hydroxyflutamide was strongly potentiated in prostate cells transfected with CBP cDNA. A functional homologue of CBP, p300, is implicated in ligand-independent AR activation by interleukin-6. The AR coactivator Tip60, which is up-regulated by androgen ablation, is recruited to the promoter of the prostate-specific antigen gene in the absence of androgen in androgen-independent prostate cancer sublines. It was proposed that the cofactor ARA70 is a specific enhancer of AR action. However, research from other laboratories has demonstrated interaction between ARA70 and other steroid receptors. Although in some cases dominant-negative coactivator mutants inhibited proliferation of prostate cancer cells in vitro, confirmation from in vivo tumour models is missing. In summary, several abnormalities in AR coactivator expression and function are associated with prostate cancer progression.
Culig
Zoran
Z
Department of Urology, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria. zoran.culig@uibk.ac.at
Comuzzi
Barbara
B
Steiner
Hannes
H
Bartsch
Georg
G
Hobisch
Alfred
A
D000123:Acetyltransferases / Q000235:genetics / Q000502:physiology; D050882:CREB-Binding Protein; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D051548:Histone Acetyltransferases; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology; D060588:LIM Domain Proteins; D000074443:Lysine Acetyltransferase 5; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology; D056920:Nuclear Receptor Coactivator 1; D051958:Nuclear Receptor Coactivator 2; D056921:Nuclear Receptor Coactivator 3; D056918:Nuclear Receptor Coactivators; D015513:Oncogene Proteins / Q000235:genetics / Q000502:physiology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000503:physiopathology*; D011944:Receptors, Androgen / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; C498001:NCOA2 protein, human; C111382:NCOA4 protein, human; D009687:Nuclear Proteins; D051958:Nuclear Receptor Coactivator 2; D056918:Nuclear Receptor Coactivators; D015513:Oncogene Proteins; C118499:RNF14 protein, human; D011944:Receptors, Androgen; C490351:TGFB1I1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D000123:Acetyltransferases; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1; D056921:Nuclear Receptor Coactivator 3