PMID- 17553165 OWN - NLM STAT- MEDLINE DCOM- 20070803 LR - 20231213 IS - 1476-4598 (Electronic) IS - 1476-4598 (Linking) VI - 6 DP - 2007 Jun 6 TI - Identification of novel androgen receptor target genes in prostate cancer. PG - 39 AB - BACKGROUND: The androgen receptor (AR) plays critical roles in both androgen-dependent and castrate-resistant prostate cancer (PCa). However, little is known about AR target genes that mediate the receptor's roles in disease progression. RESULTS: Using Chromatin Immunoprecipitation (ChIP) Display, we discovered 19 novel loci occupied by the AR in castrate resistant C4-2B PCa cells. Only four of the 19 AR-occupied regions were within 10-kb 5'-flanking regulatory sequences. Three were located up to 4-kb 3' of the nearest gene, eight were intragenic and four were in gene deserts. Whereas the AR occupied the same loci in C4-2B (castrate resistant) and LNCaP (androgen-dependent) PCa cells, differences between the two cell lines were observed in the response of nearby genes to androgens. Among the genes strongly stimulated by DHT in C4-2B cells--D-dopachrome tautomerase (DDT), Protein kinase C delta (PRKCD), Glutathione S- transferase theta 2 (GSTT2), Transient receptor potential cation channel subfamily V member 3 (TRPV3), and Pyrroline-5-carboxylate reductase 1 (PYCR1)--most were less strongly or hardly stimulated in LNCaP cells. Another AR target gene, ornithine aminotransferase (OAT), was AR-stimulated in a ligand-independent manner, since it was repressed by AR siRNA knockdown, but not stimulated by DHT. We also present evidence for in vivo AR-mediated regulation of several genes identified by ChIP Display. For example, PRKCD and PYCR1, which may contribute to PCa cell growth and survival, are expressed in PCa biopsies from primary tumors before and after ablation and in metastatic lesions in a manner consistent with AR-mediated stimulation. CONCLUSION: AR genomic occupancy is similar between LNCaP and C4-2B cells and is not biased towards 5' gene flanking sequences. The AR transcriptionally regulates less than half the genes nearby AR-occupied regions, usually but not always, in a ligand-dependent manner. Most are stimulated and a few are repressed. In general, response is stronger in C4-2B compared to LNCaP cells. Some of the genes near AR-occupied regions appear to be regulated by the AR in vivo as evidenced by their expression levels in prostate cancer tumors of various stages. Several AR target genes discovered in the present study, for example PRKCD and PYCR1, may open avenues in PCa research and aid the development of new approaches for disease management. FAU - Jariwala, Unnati AU - Jariwala U AD - Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, USA. jariwala@usc.edu FAU - Prescott, Jennifer AU - Prescott J FAU - Jia, Li AU - Jia L FAU - Barski, Artem AU - Barski A FAU - Pregizer, Steve AU - Pregizer S FAU - Cogan, Jon P AU - Cogan JP FAU - Arasheben, Armin AU - Arasheben A FAU - Tilley, Wayne D AU - Tilley WD FAU - Scher, Howard I AU - Scher HI FAU - Gerald, William L AU - Gerald WL FAU - Buchanan, Grant AU - Buchanan G FAU - Coetzee, Gerhard A AU - Coetzee GA FAU - Frenkel, Baruch AU - Frenkel B LA - eng GR - RR10600-01/RR/NCRR NIH HHS/United States GR - DK071122/DK/NIDDK NIH HHS/United States GR - P50 CA92629/CA/NCI NIH HHS/United States GR - T 32 GM067587/GM/NIGMS NIH HHS/United States GR - C06 CA062528/CA/NCI NIH HHS/United States GR - P50 CA092629/CA/NCI NIH HHS/United States GR - R01 DK071122/DK/NIDDK NIH HHS/United States GR - R01 CA109147/CA/NCI NIH HHS/United States GR - RR14514-01/RR/NCRR NIH HHS/United States GR - R56 DK071122/DK/NIDDK NIH HHS/United States GR - C06 RR014514/RR/NCRR NIH HHS/United States GR - CA62528-01/CA/NCI NIH HHS/United States GR - CA109147/CA/NCI NIH HHS/United States PT - Comparative Study PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20070606 PL - England TA - Mol Cancer JT - Molecular cancer JID - 101147698 RN - 0 (Androgens) RN - 0 (CRELD2 protein, human) RN - 0 (Cell Adhesion Molecules) RN - 0 (Extracellular Matrix Proteins) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (MRFAP1 protein, human) RN - 0 (MUC6 protein, human) RN - 0 (Mucin-6) RN - 0 (Mucins) RN - 0 (Neoplasm Proteins) RN - 0 (Nuclear Proteins) RN - 0 (Receptors, Androgen) RN - 0 (TRPV Cation Channels) RN - 0 (TRPV3 protein, human) RN - 08J2K08A3Y (Dihydrotestosterone) RN - EC 1.5.1.- (Pyrroline Carboxylate Reductases) RN - EC 2.5.1.- (GSTT2 protein, human) RN - EC 2.5.1.18 (Glutathione Transferase) RN - EC 2.6.1.13 (Ornithine-Oxo-Acid Transaminase) RN - EC 2.7.11.13 (PRKCD protein, human) RN - EC 2.7.11.13 (Protein Kinase C-delta) SB - IM MH - Adenocarcinoma/*genetics/metabolism MH - *Androgens MH - Binding Sites MH - Cell Adhesion Molecules/biosynthesis/genetics MH - Cell Line, Tumor/drug effects/metabolism MH - Chromosomes, Human/drug effects/metabolism MH - Dihydrotestosterone/pharmacology MH - Extracellular Matrix Proteins/biosynthesis/genetics MH - Gene Expression Profiling MH - *Gene Expression Regulation, Neoplastic/drug effects MH - Glutathione Transferase/biosynthesis/genetics MH - Humans MH - Intracellular Signaling Peptides and Proteins/genetics MH - Male MH - Mucin-6 MH - Mucins/biosynthesis/genetics MH - Neoplasm Proteins/biosynthesis/*genetics MH - Neoplasms, Hormone-Dependent/genetics/metabolism MH - Nuclear Proteins/biosynthesis/genetics MH - Oligonucleotide Array Sequence Analysis MH - Ornithine-Oxo-Acid Transaminase/biosynthesis/genetics MH - Prostatic Neoplasms/*genetics/metabolism MH - Protein Kinase C-delta/biosynthesis/genetics MH - Pyrroline Carboxylate Reductases/biosynthesis/genetics MH - Receptors, Androgen/genetics/*physiology MH - TRPV Cation Channels/biosynthesis/genetics MH - Transcription, Genetic MH - delta-1-Pyrroline-5-Carboxylate Reductase PMC - PMC1904239 EDAT- 2007/06/08 09:00 MHDA- 2007/08/04 09:00 PMCR- 2007/06/06 CRDT- 2007/06/08 09:00 PHST- 2007/03/13 00:00 [received] PHST- 2007/06/06 00:00 [accepted] PHST- 2007/06/08 09:00 [pubmed] PHST- 2007/08/04 09:00 [medline] PHST- 2007/06/08 09:00 [entrez] PHST- 2007/06/06 00:00 [pmc-release] AID - 1476-4598-6-39 [pii] AID - 10.1186/1476-4598-6-39 [doi] PST - epublish SO - Mol Cancer. 2007 Jun 6;6:39. doi: 10.1186/1476-4598-6-39.