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

Additional files

Additional file 1:

Figure S1. AR protein expression. VCaP cells were treated in the presence of 25nM control/non-targeted siRNA or AR-siRNA pool. The protein levels of AR were analyzed by western blot using anti-AR (Santa Cruz Cat# sc-815). Anti-Tubulin (Santa Cruz, Cat# sc-12462-R) was included for loading control. Figure S2. AR binding and cell type. Overlap of the AR binding sites between VCaP cells and other cell types from previous studies: 1(Lin et al., 2009); 2(Wang et al., 2009); 3(Massie et al., 2011). Binding sites based on earlier version of human genome were remapped to hg19 using UCSC liftOver tool. Overlap was defined by sharing of at least 1 bp. Figure S3. AR binding and sequence features. (A) Distance distribution between neighboring (10-50 bp) GREF and FKHD elements. (B) The motif identified de novo from AR-bound sequences appears to be a 15 bp perfect palindrome. (C) Motif and binding strength. AR binding sites were divided into two groups based on whether they had a significant occurrence of the palindromic motif in (B). Boxplots depict the distributions of their binding scores. Figure S4. AR and DAX1 form a tightly controlled feedback loop on steroid biosynthesis: AR and DAX1 counter-balance each other’s effect on steroidogenesis. AR also directly and positively regulates the expression of DAX1, whereas their physical interaction may serve to sense and prevent the over-production of DAX1 by AR. Dashed links refer to previously reported regulatory relationships, while solid links describe regulatory relationship identified in this study. Positive or stimulatory effects are represented by (+), and negative or inhibitory effects are represented by (−).

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Additional file 2:

sFile1. AR binding sites list.

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Additional file 3:

Table S1. The distribution of AR binding sites relative to genomic annotations. Table S2. Gene signatures most enriched among AR-bound genes. Table S3. MatBase families most over-represented among AR-bound sequences, sorted by descending Z-score. Table S4. Transcription factor binding motifs associated with mode of AR regulation. Table S5. Selective drug-modulated direct downstream effectors of AR involved in steroid metabolism.

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Additional file 4:

sFile2. Drug-modulated direct activation and repression targets of AR from small molecule antagonism.

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