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The androgen receptor cistrome is extensively reprogrammed in human prostate tumorigenesis

Nature Genetics volume 47, pages 1346–1351 (2015)Cite this article

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Abstract

Master transcription factors interact with DNA to establish cell type identity and to regulate gene expression in mammalian cells1,2. The genome-wide map of these transcription factor binding sites has been termed the cistrome3. Here we show that the androgen receptor (AR) cistrome undergoes extensive reprogramming during prostate epithelial transformation in man. Using human prostate tissue, we observed a core set of AR binding sites that are consistently reprogrammed in tumors. FOXA1 and HOXB13 colocalized at the reprogrammed AR binding sites in human tumor tissue. Introduction of FOXA1 and HOXB13 into an immortalized prostate cell line reprogrammed the AR cistrome to resemble that of a prostate tumor, functionally linking these specific factors to AR cistrome reprogramming. These findings offer mechanistic insights into a key set of events that drive normal prostate epithelium toward transformation and establish the centrality of epigenetic reprogramming in human prostate tumorigenesis.

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Figure 1: Genome-wide AR binding in normal prostate epithelium and tumor tissue.
Figure 2: Tissue-specific AR binding sites.
Figure 3: FOXA1 and HOXB13 colocalize with AR at tumor-specific AR binding sites.
Figure 4: HOXB13 and FOXA1 are sufficient for reprogramming of the AR cistrome in LHSAR cells and are essential for prostate cancer cell survival.

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Acknowledgements

We thank Z. Herbert and the Molecular Biology Core Facility at the Dana-Farber Cancer Institute for their sequencing expertise. We acknowledge funding from the Prostate Cancer Foundation (Challenge Award), the H.L. Snyder Medical Foundation (M.L.F.), US National Institutes of Health (NIH) grant R01CA193910, the Anna Fuller Fund (PS#6241901; Infoed 2013-0369), the NIH GAME-ON U19 (grant U19CA148537), the Dana-Farber Prostate Cancer Specialized Program of Research Excellence (SPORE; NIH P50CA90381-11) and the NIH grant U01CA176058 (F.V. and W.C.H.).

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Author notes

  1. Mark M Pomerantz, Fugen Li and David Y Takeda: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA

    Mark M Pomerantz, David Y Takeda, Romina Lenci, Apurva Chonkar, Matthew Chabot, Paloma Cejas, Jennifer Cook, Ramesh A Shivdasani, William C Hahn, Philip W Kantoff, Myles Brown, Massimo Loda, Henry W Long & Matthew L Freedman

  2. Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Fugen Li, Paloma Cejas, Ramesh A Shivdasani, Myles Brown, Henry W Long & Matthew L Freedman

  3. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Fugen Li

  4. The Eli and Edythe L. Broad Institute, Cambridge, Massachusetts, USA

    David Y Takeda, Francisca Vazquez, William C Hahn, Massimo Loda & Matthew L Freedman

  5. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA

    Michaela Bowden, Rosina Lis & Massimo Loda

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  1. Mark M Pomerantz
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Contributions

M.M.P. designed the study, performed ChIP-seq assays, analyzed data and wrote the manuscript. F.L. analyzed ChIP-seq data and performed biostatistical analysis. D.Y.T. performed shRNA and gene transduction experiments. A.C. and M.C. performed ChIP-seq experiments. R. Lenci performed cell line ChIP experiments. P.C. and J.C. assisted with ChIP-seq assays. R.A.S. participated in analyzing data and composing the manuscript. M.L., M. Bowden and R. Lis performed pathological analysis of radical prostatectomy specimens. W.C.H. and F.V. designed and analyzed Project Achilles and shRNA experiments. P.W.K. supplied radical prostatectomy specimens and participated in study design. M. Brown and H.W.L. contributed to study design, data analysis and manuscript composition. M.L.F. designed the study, analyzed ChIP-seq data and wrote the manuscript.

Corresponding author

Correspondence to Matthew L Freedman.

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The authors declare no competing financial interests.

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Pomerantz, M., Li, F., Takeda, D. et al. The androgen receptor cistrome is extensively reprogrammed in human prostate tumorigenesis. Nat Genet 47, 1346–1351 (2015). https://doi.org/10.1038/ng.3419

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