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Series GSE32892 Query DataSets for GSE32892
Status Public on Dec 31, 2013
Title A genome-wide and dose-dependent inhibition map of androgen receptor binding by small molecules reveals its regulatory program upon antagonism
Organism Homo sapiens
Experiment type Expression profiling by array
Genome binding/occupancy profiling by high throughput sequencing
Summary The androgen receptor plays a critical role throughout the progression of prostate cancer and is an important drug target for this disease. While chromatin immunoprecipitation coupled with massively parallel sequencing (ChIP-Seq) is becoming an essential tool in studying transcription and chromatin modification factors, it has rarely been employed in the context of drug discovery. Here we report the first publicly available genome-wide and dose-dependent inhibition landscape of AR binding by drug-like small molecules including correlation with binding strength using ChIP-Seq. Integration of sequence analysis, transcriptome profiling, cell viability assays and in vivo tumor inhibition studies enabled us to establish a direct cistrome-activity relationship for two novel potent AR antagonists. By selectively occupying the strongest binding sites, AR signaling remains active even when low androgen levels are low, a scenario characteristic of first-line androgen ablation therapy. Coupled cistrome and transcriptome profiling upon small molecule antagonism led to the identification of not only key direct downstream effectors of AR but also their mode of regulation: unbiased pathway mapping revealed that AR is a key modulator of steroid metabolism by forming a tightly controlled feedback loop with other nuclear receptor family members. Furthermore, we found AR has an extensive role in negative gene regulation and estrogen (related) receptor likely mediates its function as a transcriptional repressor. In conclusion, our study provides a global and dynamic view of AR’s regulatory program upon antagonism, which may serve as a molecular basis for deciphering and developing AR therapeutics.
Overall design GSM814034-GSM814044: Compartative study of the mRNA profiles of VCaP cells treated with small molecule inhibitor of AR and those treated with AR-siRNA

GSM817346-GSM817354: Comparative study of AR binding in VCaP cells (1) in the presence and absence of the synthetic AR agonist metribolone (R1881) and (2) in the presence of R1881 and small molecule inhibitors of AR
Contributor(s) Zhu Z, Shi M, Hu W, Estrella H, Engebretsen J, Nichols T, Briere D, Hosea N, Los G, Rejto P, Fanjul A
Citation(s) 22849360
Submission date Oct 11, 2011
Last update date May 15, 2019
Contact name Zhou Zhu
Organization name Pfizer Worldwide Research & Development
Street address 10646 Science Center Drive (CB4)
City San Diego
State/province CA
ZIP/Postal code 92121
Country USA
Platforms (2)
GPL570 [HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array
GPL9115 Illumina Genome Analyzer II (Homo sapiens)
Samples (20)
GSM814034 Vehicle, biological rep1
GSM814035 Vehicle, biological rep2
GSM814036 Vehicle, biological rep3
SRA SRP008849
BioProject PRJNA146631

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE32892_RAW.tar 49.7 Mb (http)(custom) TAR (of BED, CEL)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data included within Sample table
Processed data provided as supplementary file

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