Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/9696
Type: | Journal article |
Title: | Androgen receptor activity at the prostate specific antigen locus: Steroidal and non-steroidal mechanisms |
Author: | Jia, L. Kim, J. Shen, H. Clark, P. Tilley, W. Coetzee, G. |
Citation: | Molecular Cancer Research, 2003; 1(5):385-392 |
Publisher: | Amer Assoc Cancer Research |
Issue Date: | 2003 |
ISSN: | 1541-7786 1557-3125 |
Statement of Responsibility: | Li Jia, Joshua Kim, Howard Shen, Peter E. Clark, Wayne D. Tilley, and Gerhard A. Coetzee |
Abstract: | Ligand-activated androgen receptors (ARs) occupy target genes and recruit histone modifiers that influence transcriptional competency. In LNCaP prostate cancer cells, the natural ligand 5alpha-dihydrotestosterone (DHT) activates transiently transfected AR-responsive promoter constructs; concurrent treatment with the protein kinase A activator forskolin enhanced AR stimulation induced by DHT. Additional treatment with the cytokine IL-6, purportedly an AR activator, markedly inhibited receptor activity. To assess AR activity on natural chromatin-integrated promoters/enhancers, we determined AR occupancy of the endogenous prostate specific antigen (PSA) promoter/enhancer as well as PSA expression in LNCaP cells treated with DHT; AR occupancy of the PSA enhancer was rapid (within 1 h of stimulation), robust (10-fold over background), and sustained (8-16 h). In contrast, AR occupancy of the PSA promoter was only increased by 2-fold. Histone H3 acetylation at both the enhancer and promoter was evident 1-2 h after DHT treatment. Detectable pre- and mature PSA mRNA levels appeared after 1 and 6 h treatment, respectively. Substantial qualitative and quantitative differences in PSA expression and AR occupancy of the PSA enhancer were observed when DHT-induced and ligand-independent activations of the AR were compared; forskolin stimulated PSA mRNA and protein expression, whereas IL-6 inhibited both DHT- and forskolin-stimulated expression. IL-6 did not diminish DHT-dependent AR occupancy of the PSA enhancer but inhibited CBP/p300 recruitment, histone H3 acetylation, and cell proliferation. These findings provide a contextual framework for interpreting the contribution of non-steroidal activation of the AR to signaling in vivo, and have implications for prostate cancer cell growth. |
Keywords: | prostate cancer androgen receptor transcription IL-6 prostate specific antigen |
Rights: | © 2003 American Association for Cancer Research |
Published version: | http://mcr.aacrjournals.org/content/1/5/385.abstract? |
Appears in Collections: | Aurora harvest Medicine publications |
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