A Hierarchical Network of Transcription Factors Governs Androgen Receptor-Dependent Prostate Cancer Growth
SUMMARY
Androgen receptor (AR) is a ligand-dependent transcription factor that plays a key role in prostate cancer. Little is known about the nature of AR cis-regulatory sites in the human genome. We have mapped the AR binding regions on two chromosomes in human prostate cancer cells by combining chromatin immunoprecipitation (ChIP) with tiled oligonucleotide microarrays. We find that the majority of AR binding regions contain noncanonical AR-responsive elements (AREs). Importantly, we identify a noncanonical ARE as a cis-regulatory target of AR action in TMPRSS2, a gene fused to ETS transcription factors in the majority of prostate cancers. In addition, through the presence of enriched DNA-binding motifs, we find other transcription factors including GATA2 and Oct1 that cooperate in mediating the androgen response. These collaborating factors, together with AR, form a regulatory hierarchy that governs androgen-dependent gene expression and prostate cancer growth and offer potential new opportunities for therapeutic intervention.
Footnotes
Supplemental Data
Supplemental Data include Supplemental Experimental Procedures, seven figures, and four tables and can be found with this article online at http://www.molecule.org/cgi/content/full/27/3/380/DC1/.
Accession Numbers
The microarray data in this study have been deposited in NCBI's Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo/) and are accessible under GEO Series accession number {"type":"entrez-geo","attrs":{"text":"GSE7868","term_id":"7868"}}GSE7868.