Androgen Modulation of Coregulator Expression in Prostate Cancer Cells

Hannelore V. Heemers, Kevin M. Regan, Lucy J. Schmidt, S. Keith Anderson, Karla V. Ballman, Donald J. Tindall

Research output: Contribution to journalArticle

59 Scopus citations

Abstract

Aberrant coregulator expression that occurs during prostate cancer (PCa) progression correlates with poor prognosis and aggressive disease. This has been attributed to the ability to regulate androgen receptor-mediated transcription. We have shown previously that the androgenic milieu regulates the expression of the coactivators p300 and FHL2, with severe consequences for PCa cell proliferation and androgen receptor transcriptional activity.Todetermine the extent ofandrogen dependencyofcoregulator genes, wedesigned a cDNA-mediated annealing, selection, extension, and ligation RNA profiling array that probes the expression of 186 coregulators. Using this assay, we demonstrated androgen control over approximately 30% of coregulator genesinPCa cells. For a subset of 15 functionally diverse coregulators, androgen regulation was confirmed using realtime RT-PCR and immunoblotting. The extent, dose dependency, and kinetics by which androgens affect coregulator expression differed widely, indicating diverse molecular mechanisms underlying these effects. Moreover, differences in coregulator expression were observed between isogenic androgen-dependent and castration-recurrent PCa cells. Small interfering RNA-mediated changes in coregulator expression had profound effects on cell proliferation, which were most pronounced in castration-recurrent cells. Taken together, our integrated approach combining expression profiling, characterization of androgen-dependent coregulator expression, and validation of the importance of altered coregulator expression for cell proliferation identified several potential novel therapeutic targets for PCa treatment. (Molecular Endocrinology 23: 572-583, 2009)

Original languageEnglish (US)
Pages (from-to)572-583
Number of pages12
JournalMolecular Endocrinology
Volume23
Issue number4
DOIs
StatePublished - Apr 1 2009

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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    Heemers, H. V., Regan, K. M., Schmidt, L. J., Anderson, S. K., Ballman, K. V., & Tindall, D. J. (2009). Androgen Modulation of Coregulator Expression in Prostate Cancer Cells. Molecular Endocrinology, 23(4), 572-583. https://doi.org/10.1210/me.2008-0363