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Updated: Jun 21, 2026
Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer
Published on: March 17, 2016
Integrated expression profiling and ChIP-seq analyses of the growth inhibition response program of the androgen
Biaoyang Lin1, Jun Wang, Xu Hong
1Department of Urology, University of Washington, Seattle, WA, USA. biaoylin@gmail.com
Background:
The androgen receptor (AR) plays important roles in the development of male phenotype and in different human diseases including prostate cancers. The AR can act either as a promoter or a tumor suppressor depending on cell types. The AR proliferative response program has been well studied, but its prohibitive response program has not yet been thoroughly studied.
Methodology/Principal Findings:
Previous studies found that PC3 cells expressing the wild-type AR inhibit growth and suppress invasion. We applied expression profiling to identify the response program of PC3 cells expressing the AR (PC3-AR) under different growth conditions (i.e. with or without androgens and at different concentration of androgens) and then applied the newly developed ChIP-seq technology to identify the AR binding regions in the PC3 cancer genome. A surprising finding was that the comparison of MOCK-transfected PC3 cells with AR-transfected cells identified 3,452 differentially expressed genes (two fold cutoff) even without the addition of androgens (i.e. in ethanol control), suggesting that a ligand independent activation or extremely low-level androgen activation of the AR. ChIP-Seq analysis revealed 6,629 AR binding regions in the cancer genome of PC3 cells with an FDR (false discovery rate) cut off of 0.05. About 22.4% (638 of 2,849) can be mapped to within 2 kb of the transcription start site (TSS). Three novel AR binding motifs were identified in the AR binding regions of PC3-AR cells, and two of them share a core consensus sequence CGAGCTCTTC, which together mapped to 27.3% of AR binding regions (1,808/6,629). In contrast, only about 2.9% (190/6,629) of AR binding sites contains the canonical AR matrix M00481, M00447 and M00962 (from the Transfac database), which is derived mostly from AR proliferative responsive genes in androgen dependent cells. In addition, we identified four top ranking co-occupancy transcription factors in the AR binding regions, which include TEF1 (Transcriptional enhancer factor), GATA (GATA transcription factors), OCT (octamer transcription factors) and PU1 (PU.1 transcription factor).
Conclusions/Significance:
Our data provide a valuable data set in understanding the molecular basis for growth inhibition response program of the AR in prostate cancer cells, which can be exploited for developing novel prostate cancer therapeutic strategies.
Insights
Androgen receptor (AR) plays a dual role in prostate cancer. This study identified novel AR binding sites and motifs, revealing insights into AR
Area of Science:
- Molecular Biology
- Genomics
- Cancer Research
Background:
- The androgen receptor (AR) is crucial for male development and implicated in prostate cancer.
- AR's role as a tumor promoter or suppressor varies by cell type.
- The AR's growth-inhibitory functions are less understood than its proliferative effects.
Purpose of the Study:
- To investigate the AR's prohibitive response program in prostate cancer cells.
- To identify AR binding regions and gene expression changes in PC3 prostate cancer cells.
- To discover novel AR binding motifs and co-occupying transcription factors.
Main Methods:
- Expression profiling of PC3 cells with and without AR transfection and androgens.
- ChIP-seq technology to map AR binding regions in the PC3 cancer genome.
- Bioinformatic analysis to identify differentially expressed genes, AR binding sites, and motifs.
Main Results:
- 3,452 differentially expressed genes were identified in AR-transfected PC3 cells, even without androgens, suggesting ligand-independent AR activation.
- ChIP-seq identified 6,629 AR binding regions, with 22.4% near transcription start sites.
- Three novel AR binding motifs were discovered, with two sharing a CGAGCTCTTC core sequence; canonical AR motifs were less prevalent.
- TEF1, GATA, OCT, and PU1 were identified as top co-occupancy transcription factors.
Conclusions:
- This study provides a comprehensive dataset on the AR's molecular mechanisms in prostate cancer growth inhibition.
- The findings offer a foundation for developing novel therapeutic strategies targeting AR signaling in prostate cancer.
- Identification of novel AR binding motifs and co-factors advances our understanding of AR regulation.
