دورية أكاديمية

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

التفاصيل البيبلوغرافية
العنوان: Dose-dependent effects of small-molecule antagonists on the genomic landscape of androgen receptor binding
المؤلفون: Zhu Zhou, Shi Manli, Hu Wenyue, Estrella Heather, Engebretsen Jon, Nichols Tim, Briere David, Hosea Natilie, Los Gerrit, Rejto Paul A, Fanjul Andrea
المصدر: BMC Genomics, Vol 13, Iss 1, p 355 (2012)
بيانات النشر: BMC
سنة النشر: 2012
المجموعة: Directory of Open Access Journals: DOAJ Articles
مصطلحات موضوعية: Androgen receptor, ChIP-Seq, Prostate cancer, AR antagonist, Molecular profiling, Biotechnology, TP248.13-248.65, Genetics, QH426-470
الوصف: 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. 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. 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.
نوع الوثيقة: article in journal/newspaper
اللغة: English
تدمد: 1471-2164
العلاقة: http://www.biomedcentral.com/1471-2164/13/355Test; https://doaj.org/toc/1471-2164Test; https://doaj.org/article/7cc37779c83245cb9ff3d3e41a4a2014Test
DOI: 10.1186/1471-2164-13-355
الإتاحة: https://doi.org/10.1186/1471-2164-13-355Test
https://doaj.org/article/7cc37779c83245cb9ff3d3e41a4a2014Test
رقم الانضمام: edsbas.FA79EF99
قاعدة البيانات: BASE
الوصف
تدمد:14712164
DOI:10.1186/1471-2164-13-355