Cyclin D1 Is a Selective Modifier of Androgen-dependent Signaling and Androgen Receptor Function

Clay E. S. Comstock; Michael A. Augello; Matthew J. Schiewer; Jason Karch; Craig J. Burd; Adam Ertel; Erik S. Knudsen; Walter J. Jessen; Bruce J. Aronow; Karen E. Knudsen

doi:10.1074/jbc.M110.170720

Cyclin D1 Is a Selective Modifier of Androgen-dependent Signaling and Androgen Receptor Function*

From the ^‡Kimmel Cancer Center,
^§Department of Cancer Biology,
^§§Department of Urology, and
^¶¶Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107,
the ^¶Department of Cell and Cancer Biology, University of Cincinnati, Cincinnati, Ohio 45221,
^‖NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709,
the ^**Covance Biomarker Center of Excellence, Greenfield, Indiana 46140, and
^‡‡Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229

1 To whom correspondence should be addressed: 233 S. 10th St., BLSB 1008A, Philadelphia, PA 19107. Tel.: 215-503-8574; Fax: 215-923-4498; E-mail: Karen.Knudsen{at}kimmelcancercenter.org.

Abstract

D-type cyclins regulate cellular outcomes in part through cyclin-dependent, kinase-independent mechanisms that modify transcription factor action, and recent in vivo studies showed that cyclin D1 associates with a large number of transcriptional regulators in cells of the retina and breast. Given the frequency of cyclin D1 alterations in cancer, it is imperative to delineate the molecular mechanisms by which cyclin D1 controls key transcription factor networks in human disease. Prostate cancer was used as a paradigm because this tumor type is reliant at all stages of the disease on androgen receptor (AR) signaling, and cyclin D1 has been shown to negatively modulate AR-dependent expression of prostate-specific antigen (KLK3/PSA). Strategies were employed to control cyclin D1 expression under conditions of hormone depletion, and the effect of cyclin D1 on subsequent androgen-dependent gene expression was determined using unbiased gene expression profiling. Modulating cyclin D1 conferred widespread effects on androgen signaling and revealed cyclin D1 to be a selective effector of hormone action. A subset of androgen-induced target genes, known to be directly regulated by AR, was strongly suppressed by cyclin D1. Analyses of AR occupancy at target gene regulatory loci of clinical relevance demonstrated that cyclin D1 limits AR residence after hormone stimulation. Together, these findings reveal a new function for cyclin D1 in controlling hormone-dependent transcriptional outcomes and demonstrate a pervasive role for cyclin D1 in regulating transcription factor dynamics.

Footnotes

↵* This work was supported, in whole or in part, by National Institutes of Health Grant CA099996 (to K. E. K.). This work was also supported by Department of Defense New Investigator Award PC094507 (to C. E. S. C.) and Department of Defense Predoctoral Fellowships PC094195 (to M. J. S.) and PC094596 (to M. A. A.).
↵ The on-line version of this article (available at http://www.jbc.org) contains supplemental Table 1 and Figs. 1–3.