Open Access Research article

Dose-dependent effects of small-molecule antagonists on the genomic landscape of androgen receptor binding

Zhou Zhu1*, Manli Shi1, Wenyue Hu2, Heather Estrella1, Jon Engebretsen1, Tim Nichols2, David Briere1, Natilie Hosea3, Gerrit Los1, Paul A Rejto1 and Andrea Fanjul1*

Author Affiliations

1 Oncology Research Unit, Pfizer Worldwide Research & Development, La Jolla Laboratories, San Diego, CA, 92121, USA

2 Drug Safety Research & Development, Pfizer Worldwide Research & Development, La Jolla Laboratories, San Diego, CA, 92121, USA

3 Pharmacokinetics, Dynamics & Metabolism, Pfizer Worldwide Research & Development, La Jolla Laboratories, San Diego, CA, 92121, USA

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BMC Genomics 2012, 13:355  doi:10.1186/1471-2164-13-355

Published: 31 July 2012



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 for studying transcription and chromatin modification factors, it has rarely been employed in the context of drug discovery.


Here we report changes in the genome-wide AR binding landscape due to dose-dependent inhibition by drug-like small molecules using ChIP-Seq. Integration of sequence analysis, transcriptome profiling, cell viability assays and xenograft tumor growth 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 androgen levels are low, as is characteristic of first-line androgen ablation therapy. Coupled cistrome and transcriptome profiling upon small molecule antagonism led to the identification of a core set of AR direct effector genes that are most likely to mediate the activities of targeted agents: 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 and this oncogenic effect can be relieved by antagonist treatment. Furthermore, we found that AR also has an extensive role in negative gene regulation, with estrogen (related) receptor likely mediating its function as a transcriptional repressor.


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.

Androgen receptor; ChIP-Seq; Prostate cancer; AR antagonist; Molecular profiling