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Prostate cancer (PCa) is the most common non-cutaneous cancer in men. The androgen receptor (AR), a ligand-activated transcription factor, constitutes the main drug target for advanced cases of the disease. However, a variety of other transcription factors and signaling networks have been shown to be altered in patients and to influence AR activity. Amongst these, the oncogenic transcription factor c-Myc has been studied extensively in multiple malignancies and elevated protein levels of c-Myc are commonly observed in PCa. Its impact on AR activity, however, remains elusive. In this study, we assessed the impact of c-Myc overexpression on AR activity and transcriptional output in a PCa cell line model and validated the antagonistic effect of c-MYC on AR-targets in patient samples. We found that c-Myc overexpression partially reprogrammed AR chromatin occupancy and was associated with altered histone marks distribution, most notably H3K4me1 and H3K27me3. We found c-Myc and the AR co-occupy a substantial number of binding sites and these exhibited enhancer-like characteristics. Interestingly, c-Myc overexpression antagonised clinically relevant AR target genes. Therefore, as an example, we validated the antagonistic relationship between c-Myc and two AR target genes, KLK3 (alias PSA, prostate specific antigen), and Glycine N-Methyltransferase (GNMT), in patient samples. Our findings provide unbiased evidence that MYC overexpression deregulates the AR transcriptional program, which is thought to be a driving force in PCa.

Original publication

DOI

10.1016/j.ebiom.2017.04.006

Type

Journal article

Journal

EBioMedicine

Publication Date

04/2017

Volume

18

Pages

83 - 93

Keywords

Androgen receptor, Chromatin immunoprecipitation exonuclease (ChIP-exo), DNA damage, Glycine N-Methyltransferase (GNMT), Prostate cancer, c-Myc, Binding Sites, Cell Line, Tumor, Chromatin, Cluster Analysis, Disease-Free Survival, Down-Regulation, Gene Regulatory Networks, Glycine N-Methyltransferase, Histones, Humans, Immunohistochemistry, Kallikreins, Kaplan-Meier Estimate, Male, Prostate-Specific Antigen, Prostatic Neoplasms, Proto-Oncogene Proteins c-myc, RNA Interference, RNA, Small Interfering, Receptors, Androgen, Transcription Factors, Transcription, Genetic, Up-Regulation