Genome-Wide Analysis of Transcription Factor Function in Prostate Cancer

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): 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 improve our understanding of the combinatorial transcriptional regulation of target genes by AR, its collaborating transcription factors and its coactivators from a genome-wide view in androgen-dependent (AD) and -independent (Al) prostate cancer cells. To address these issures, 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 factor ChlP-on-chip will be performed and correlated with AR ChlP-on-chip and gene expression profiles to identify combinatorial transcriptional regulatory codes and mechanisms for AR target genes in AD and Al prostate cancer cells. The combinatorial regulation results from prostate cancer cell lines will be correlated with mircroarray data from clinical samples to verify clinical relevance. (3) Determine how coactivators play coregulatory roles in selected novel AR target genes identified from aim 1 and aim 2. The physical interactions among coactivators, AR and collaborating factors will be studied. The functional roles of coactivators in AR and collaborating factors binding, target gene expression and prostate cancer cell growth and survival will be determined. These studies will define the mechanisms underlying the differential transcriptional regulation of target genes by AR, collaborating transcription factors and coactivators in AD and Al prostate cancer and will lead to the identification of new molecular targets for therapeutic intervention.