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Prostate cancer is the most common cancer in men, resulting in over 10 000 deaths/year in the UK. Sequencing and copy number analysis of primary tumours has revealed heterogeneity within tumours and an absence of recurrent founder mutations, consistent with non-genetic disease initiating events. Using methylation profiling in a series of multi-focal prostate tumours, we identify promoter methylation of the transcription factor HES5 as an early event in prostate tumourigenesis. We confirm that this epigenetic alteration occurs in 86-97% of cases in two independent prostate cancer cohorts (n=49 and n=39 tumour-normal pairs). Treatment of prostate cancer cells with the demethylating agent 5-aza-2'-deoxycytidine increased HES5 expression and downregulated its transcriptional target HES6, consistent with functional silencing of the HES5 gene in prostate cancer. Finally, we identify and test a transcriptional module involving the AR, ERG, HES1 and HES6 and propose a model for the impact of HES5 silencing on tumourigenesis as a starting point for future functional studies.

Original publication

DOI

10.1530/ERC-14-0454

Type

Journal article

Journal

Endocr Relat Cancer

Publication Date

04/2015

Volume

22

Pages

131 - 144

Keywords

AR, ERG, HES5, HES6, NOTCH, epigenetics, methylation, prostate cancer, Basic Helix-Loop-Helix Transcription Factors, Carcinogenesis, Cell Line, Tumor, DNA Methylation, Epigenesis, Genetic, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Male, Promoter Regions, Genetic, Prostatic Neoplasms, Repressor Proteins, Trans-Activators, Transcriptional Regulator ERG