HES5 silencing is an early and recurrent change in prostate tumourigenesis

Endocr Relat Cancer. 2015 Apr;22(2):131-44. doi: 10.1530/ERC-14-0454. Epub 2015 Jan 5.

Abstract

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.

Keywords: AR; ERG; HES5; HES6; NOTCH; epigenetics; methylation; prostate cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Carcinogenesis / genetics*
  • Cell Line, Tumor
  • DNA Methylation
  • Epigenesis, Genetic
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Promoter Regions, Genetic
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / metabolism
  • Repressor Proteins / genetics*
  • Trans-Activators / genetics
  • Transcriptional Regulator ERG

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • ERG protein, human
  • Repressor Proteins
  • Trans-Activators
  • Transcriptional Regulator ERG
  • HES5 protein, human