Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of human LNCaP cell line

ABSTRACT: Androgen receptor (AR) is a ligand-dependent transcription factor that plays a key role in the onset and progression of prostate cancer. Surprisingly little is known of AR binding sites and collaborating transcription factors in the human genome. Here we have identified the DNA sequence motifs that are significantly enriched within the authentic 90 AR target regions found on chromosomes 21 and 22 in human prostate cancer cells by combining chromatin immunoprecipitation for AR with chromosome-scale tiled oligonucleotide microarrays. By integrating the DNA sequence motif data with the gene expression profiles from human prostate cancers we identified the transcription factors that recognize each of these motifs. These factors form complexes with AR, bind to specific AR target regions and govern androgen-dependent transcription. Together with AR these collaborating transcription factors form a regulatory network that directs prostate cancer growth and survival and identify potential new opportunities for therapeutic intervention. Experiment Overall Design: The RNA samples are extracted from DHT 0, 4h and 16h treated LNCaP cells by using a RNeasy kit (Qiagen). The final RNAs submitted to Dana-Farber Cancer Institute (DFCI) Microarray Core Facility are all at 1.5ug/ul, A260/A280=2.1.

ORGANISM(S): Homo sapiens

SUBMITTER: Wei Li

PROVIDER: E-GEOD-7868 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

A hierarchical network of transcription factors governs androgen receptor-dependent prostate cancer growth.

Wang Qianben Q Li Wei W Liu X Shirley XS Carroll Jason S JS Jänne Olli A OA Keeton Erika Krasnickas EK Chinnaiyan Arul M AM Pienta Kenneth J KJ Brown Myles M

Molecular cell 20070801 3

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 noncan ...[more]

PMID: 17679089

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Project description:The androgen receptor (AR) is a mediator of both androgen-dependent and castration- resistant prostate cancers. Identification of cellular factors affecting AR transcriptional activity could in principle yield new targets that reduce AR activity and combat prostate cancer, yet a comprehensive analysis of the genes required for AR-dependent transcriptional activity has not been determined. Using an unbiased genetic approach that takes advantage of the evolutionary conservation of AR signaling, we have conducted a genome-wide RNAi screen in Drosophila cells for genes required for AR transcriptional activity and applied the results to human prostate cancer cells. We identified 45 AR-regulators, which include known pathway components and genes with functions not previously linked to AR regulation, such as HIPK2 (a protein kinase) and MED19 (a subunit of the Mediator complex). Depletion of HIPK2 and MED19 in human prostate cancer cells decreased AR target gene expression and, importantly, reduced the proliferation of androgen-dependent and castration-resistant prostate cancer cells. We also systematically analyzed additional Mediator subunits and uncovered a small subset of Mediator subunits that interpret AR signaling and affect AR-dependent transcription and prostate cancer cell proliferation. Importantly, targeting of HIPK2 by an FDA approved kinase inhibitor phenocopied the effect of depletion by RNAi and reduced the growth of AR-positive, but not AR negative, treatment-resistant prostate cancer cells. Thus, our screen has yielded new AR regulators including drugable targets that reduce the proliferation of castration-resistant prostate cancer cells. HIPK2 and MED19 were identified via a genome-wide RNAi screen as new androgen receptor (AR) reulators. Our goal in performing this microarray was to identify the gene regulated by HIPK2 and MED19 in a late stage prostate cancer cell line (LNCaP-abl), and to see what genes are in common with known genes to be regulated by AR, and what genes are unique to HIPK2 or MED19. Knockdown of HIPK2 and MED19 was tested in LNCaP-abl cells against control. Each was performed in duplicates. Six samples were analyzed

Dataset Information

Transcription profiling of human LNCaP cell line

Publications

A hierarchical network of transcription factors governs androgen receptor-dependent prostate cancer growth.

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