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Dose-dependent effects of small-molecule antagonists on the genomic landscape of androgen receptor binding.
- Source :
-
BMC genomics [BMC Genomics] 2012 Jul 31; Vol. 13, pp. 355. Date of Electronic Publication: 2012 Jul 31. - Publication Year :
- 2012
-
Abstract
- Background: 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.<br />Results: 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.<br />Conclusions: 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.
- Subjects :
- Androgen Receptor Antagonists therapeutic use
Androgen Receptor Antagonists toxicity
Animals
Binding Sites
Cell Line, Tumor
Cell Survival drug effects
Chromatin Immunoprecipitation
Chromosome Mapping
Dose-Response Relationship, Drug
Humans
Male
Mice
Mice, SCID
Prostatic Neoplasms drug therapy
Protein Binding
Receptors, Androgen chemistry
Receptors, Androgen genetics
Sequence Analysis, DNA
Small Molecule Libraries therapeutic use
Small Molecule Libraries toxicity
Transplantation, Heterologous
Androgen Receptor Antagonists metabolism
Receptors, Androgen metabolism
Small Molecule Libraries metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1471-2164
- Volume :
- 13
- Database :
- MEDLINE
- Journal :
- BMC genomics
- Publication Type :
- Academic Journal
- Accession number :
- 22849360
- Full Text :
- https://doi.org/10.1186/1471-2164-13-355