The androgen receptor (AR), a ligand-dependent transcription factor, plays a key role in the onset and progression of prostate cancer and is a therapeutic target. Surprisingly little is known of AR binding, AR collaborating transcription factors, and regulation of AR target genes in the human genome. The overall goal of this proposal is to investigate the combinatorial transcriptional regulation of protein-coding genes and a class of non-coding genes (microRNA [miRNA]) by AR and its collaborating transcription factors from a genome-wide view in androgen-dependent (AD) and -independent (Al) prostate cancer cells. To address these issues, we will use chromatin immunoprecipitation (ChIP) combined with human whole genome interrogating tiling microarrays (ChlP-on-chip) to study in vivo binding of transcription factors and their regulatory function in AD and Al prostate cancer.
Our specific aims are to: (1) Determine whether distinct AR binding, AR collaborating transcription factor partners and AR target genes exist in AD and Al prostate cancer cells. AR ChlP-on-chip assays will be performed in AD and Al prostate cancer cells. AR binding, its collaborating transcription factors and AR target genes will be predicted by bioinformatics algorithms and experimentally validated. (2) Determine how AR and its collaborating transcription factors combinatorially regulate AR target genes in AD and Al prostate cancer cells. Collaborating transcription factors ChlP-on-chip will be performed and correlated with AR ChlP-on-chip and gene expression profiles to identify combinatorial transcriptional regulatory codes for AR target genes in AD and Al prostate cancer cells. (3) Determine whether AR and its collaborating transcription factors regulate miRNAs in AD versus Al prostate cancer cells. RNA polymerase II (pol II) ChlP-on-chip will be performed in AD and Al prostate cancer cells. Pol II binding will be correlated to AR and its collaborating transcription factors bindings and miRNA expression profiles to identify differential transcription factors-regulated miRNA expression in AD and Al prostate cancer cells. In summary, these studies will increase our fundamental understanding of differential transcriptional regulation of target coding and non-coding genes by AR and its collaborating transcription factors on a genome-wide level in AD and Al prostate cancer, which will lead to identification of new molecular targets for therapeutic intervention in AD and Al prostate cancer.
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