Abstract
BackgroundThe 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.ResultsUsing 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.ConclusionAR 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.
Highlights
The androgen receptor (AR) plays critical roles in both androgen-dependent and castrate-resistant prostate cancer (PCa)
Several AR target genes discovered in the present study, for example Protein kinase C delta (PRKCD) and Pyrroline-5-carboxylate reductase 1 (PYCR1), may open avenues in PCa research and aid the development of new approaches for disease management
We have identified 19 novel AR-occupied regions in PCa cells, many of which are associated with genes that are regulated by the AR in either a ligand-dependent or ligandindependent manner
Summary
The androgen receptor (AR) plays critical roles in both androgen-dependent and castrate-resistant prostate cancer (PCa). Differentiation and apoptosis the androgen receptor (AR) plays a pivotal role in PCa progression, as well as in normal prostate development [2,3,4]. AR-mediated PCa growth is initially hormone-dependent, and men failing surgical and radiation therapy are subjected to androgen ablation therapy [5]. Androgen ablation in these cases almost always leads to tumor regression, but this is inevitably followed by recurrence of PCa due to the development of castrateresistant and often metastatic disease. Specific expression in mouse prostate epithelial cells of an AR transgene containing a gain-offunction mutation (with increased basal activity and response to coregulators), resulted in PCa development in 100% of the animals [10] proving that aberrant AR signaling was sufficient to cause PCa and that under certain conditions the AR acts as an oncogene
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