The androgen receptor cistrome is extensively reprogrammed in human prostate tumorigenesis

• Published in: Nature genetics Vol. 47; no. 11; pp. 1346 - 1351
• Main Authors: Pomerantz, Mark M, Li, Fugen, Takeda, David Y, Lenci, Romina, Chonkar, Apurva, Chabot, Matthew, Cejas, Paloma, Vazquez, Francisca, Cook, Jennifer, Shivdasani, Ramesh A, Bowden, Michaela, Lis, Rosina, Hahn, William C, Kantoff, Philip W, Brown, Myles, Loda, Massimo, Long, Henry W, Freedman, Matthew L
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2015; Nature Publishing Group
• Subjects: 13/89; 45/15; 45/61; 631/208/176; 692/699/67/589/466; 82/51; Agriculture; Animal Genetics and Genomics; Binding sites; Binding Sites - genetics; Biomedicine; Cancer; Cancer Research; Carcinogenesis - genetics; Carcinogenesis - metabolism; Cell Line, Tumor; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Chromatin Immunoprecipitation; Cluster Analysis; Development and progression; Epigenetic inheritance; Experiments; Gene expression; Gene Function; Gene mutations; Genetic aspects; Genetic research; Genome-Wide Association Study - methods; Genomes; Health aspects; Hepatocyte Nuclear Factor 3-alpha - genetics; Hepatocyte Nuclear Factor 3-alpha - metabolism; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Hormone receptors; Human Genetics; Humans; Immunoblotting; Kaplan-Meier Estimate; letter; Male; Oncology, Experimental; Prostate - metabolism; Prostate - pathology; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Protein Binding; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; RNA Interference; Sequence Analysis, DNA; Transcriptome - genetics; Tumorigenesis; Tumors
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.3419

Matthew Freedman and colleagues show that androgen receptor (AR) binding sites undergo extensive reprogramming during prostate epithelial transformation. They further show that FOXA1 and HOXB13 colocalize at reprogrammed AR binding sites in human tumor tissue and are able to reprogram the AR cistrome of an immortalized prostate cell line to resemble that of prostate tumors. Master transcription factors interact with DNA to establish cell type identity and to regulate gene expression in mammalian cells 1 , 2 . The genome-wide map of these transcription factor binding sites has been termed the cistrome 3 . 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.