Baruch Frenkel holds the J. Harold and Edna L. LaBriola Chair in Genetic Orthopaedic Research at the University of Southern California.
Version of Record online: 11 JUL 2007
Copyright © 2007 Wiley-Liss, Inc.
Volume 67, Issue 13, pages 1371–1383, 15 September 2007
How to Cite
Prescott, J., Jariwala, U., Jia, L., Cogan, J. P., Barski, A., Pregizer, S., Shen, H. C., Arasheben, A., Neilson, J. J., Frenkel, B. and Coetzee, G. A. (2007), Androgen receptor-mediated repression of novel target genes. Prostate, 67: 1371–1383. doi: 10.1002/pros.20623
Baruch Frenkel and Gerhard A. Coetzee co-directed the study.
- Issue online: 26 JUL 2007
- Version of Record online: 11 JUL 2007
- Manuscript Accepted: 11 MAY 2007
- Manuscript Received: 20 FEB 2007
- United States Department of Defense. Grant Numbers: W81XWH-04-1-0823, W81XWH-05-1-0025
- NIH. Grant Numbers: R01 CA109147, R01 DK071122, T32 GM067587
- The Prostate Cancer Foundation
- Research Facilities Improvement Program from the NIH/NCRR. Grant Number: C06 (RR10600-01, CA62528-01, RR14514-01)
- prostate cancer;
- androgen receptor;
- target genes;
- ChIP Display
The androgen receptor (AR) plays a pivotal role in prostate cancer (PCa) initiation and progression. To date, studies have focused disproportionately on androgen-stimulated genes such as prostate-specific antigen (PSA), while repressed genes have gained little attention, even though they too may be involved in regulating cell growth, differentiation, and apoptosis.
ChIP Display was used to identify putative AR target genes in the ablation-resistant human PCa cell line, C4-2B. Quantitative real-time reverse transcription-PCR analysis was used to measure gene expression in cells subjected to dihydrotestosterone (DHT) timecourse and dose–response, as well as AR knock-down and bicalutamide-treatments.
We report on three genes, KIAA1217, CHRM1, and WBSCR28, which were newly identified in a screen for AR-occupied regions in C4-2B PCa cells, and which were repressed by treatment with DHT. AR knock-down resulted in increased KIAA1217, CHRM1, and WBSCR28 mRNA, indicating that, like PSA stimulation, AR represses these three genes even in the absence of added ligand. DHT decreased KIAA1217 and CHRM1 pre-mRNA levels, suggesting AR-mediated transcriptional inhibition. Cycloheximide attenuated DHT-mediated repression of CHRM1, suggesting the requirement of new protein synthesis. Furthermore, bicalutamide treatment did not mimic, but rather antagonized DHT-mediated KIAA1217 repression. Unlike the handful of androgen-repressed genes studied thus far, AR occupancy at KIAA1217, CHRM1, and WBSCR28 was mapped outside their respective 5′-promoter regions.
Many more genes likely share AR-mediated gene repression through distal regulatory elements. Further study of such targets and their transcriptional regulation may help explain the receptor's tumorigenicity in PCa. Prostate 67: 1371–1383, 2007. © 2007 Wiley-Liss, Inc.