Androgen receptor activity at the prostate specific antigen locus: Steroidal and non-steroidal mechanisms

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dc.contributor.authorJia, L.
dc.contributor.authorKim, J.
dc.contributor.authorShen, H.
dc.contributor.authorClark, P.
dc.contributor.authorTilley, W.
dc.contributor.authorCoetzee, G.
dc.date.issued2003
dc.description.abstractLigand-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.
dc.description.statementofresponsibilityLi Jia, Joshua Kim, Howard Shen, Peter E. Clark, Wayne D. Tilley, and Gerhard A. Coetzee
dc.identifier.citationMolecular Cancer Research, 2003; 1(5):385-392
dc.identifier.issn1541-7786
dc.identifier.issn1557-3125
dc.identifier.orcidTilley, W. [0000-0003-1893-2626]
dc.identifier.urihttp://hdl.handle.net/2440/9696
dc.language.isoen
dc.publisherAmer Assoc Cancer Research
dc.rights© 2003 American Association for Cancer Research
dc.source.urihttp://mcr.aacrjournals.org/content/1/5/385.abstract?
dc.subjectprostate cancer
dc.subjectandrogen receptor
dc.subjecttranscription
dc.subjectIL-6
dc.subjectprostate specific antigen
dc.titleAndrogen receptor activity at the prostate specific antigen locus: Steroidal and non-steroidal mechanisms
dc.typeJournal article
pubs.publication-statusPublished

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