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Submitted on June 16, 2004
Accepted on August 4, 2004
Biomedicum Helsinki, Institute of Biomedicine (Z.K., O.A.J., J.J.P.), and Department of Clinical Chemistry (O.A.J.), University of Helsinki and University of Helsinki Central Hospital, FI-00014 Helsinki, Department of Medical Biochemistry (J.J.P.), University of Kuopio, FI-70211, Kuopio, Finland
* To whom correspondence should be addressed. E-mail: jorma.palvimo{at}helsinki.fi.
We have used chromatin immunoprecipitation (ChIP) assay to follow transcription factor loading and monitor changes in covalent histone modifications associated with the prostate-specific antigen (PSA) and kallikrein (KLK2) genes in response to androgen and antiandrogen in LNCaP cells. The dynamics of testosterone (T)-induced loading of AR onto the proximal promoters of the genes differed significantly from that onto the distal enhancers. Significantly more holo-AR was loaded onto the enhancers than the promoters, but the receptor's residence time was more transient on the enhancers. Even though holo-AR recruited some RNA polymerase II (Pol II) onto the enhancers, the principal Pol II transcription complex was assembled on the promoters. The pure antiandrogen bicalutamide (CDX) complexed to AR elicited occupancy of the PSA promoter, but not that of the enhancer, whereas the partial antagonists cyproterone acetate (CPA) and mifepristone (RU486) were capable of promoting AR loading also onto the enhancer. In contrast to the CDX-occupied receptor, both CPA- and RU486-bound AR recruited Pol II and coactivators p300 and GRIP1 onto the promoter and enhancer. However, CPA and RU486 also brought about a simultaneous recruitment of the corepressor NCoR onto the promoter as efficiently as CDX. There were dynamic changes in covalent modifications of histone H3: acetylation of lysine 9 and 14, methylation of arginine 17, phosphorylation of serine 10 as well as di- and tri-methylation at lysine 4 of the H3 N-terminal tail were enhanced in response to T, but not after CDX treatment. Collectively, these results indicate that transcriptional activation by AR is accompanied by a cascade of distinct covalent histone modifications and that the pure antiandrogen CDX and the partial antagonists CPA and RU486 exhibit clear differences in their ability to promote recruitment of histone-acetylating and histone-deacetylating complexes in human prostate cancer cells.
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