TY - JOUR
T1 - Androgen Modulation of Coregulator Expression in Prostate Cancer Cells
AU - Heemers, Hannelore V.
AU - Regan, Kevin M.
AU - Schmidt, Lucy J.
AU - Anderson, S. Keith
AU - Ballman, Karla V.
AU - Tindall, Donald J.
PY - 2009/4
Y1 - 2009/4
N2 - 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)
AB - 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)
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U2 - 10.1210/me.2008-0363
DO - 10.1210/me.2008-0363
M3 - Article
C2 - 19164447
AN - SCOPUS:64749107759
SN - 0888-8809
VL - 23
SP - 572
EP - 583
JO - Molecular Endocrinology
JF - Molecular Endocrinology
IS - 4
ER -