HES5 silencing is an early and recurrent change in prostate tumourigenesis

Charles E. Massie*, Inmaculada Spiteri, Helen Ross-Adams, Hayley Luxton, Jonathan Kay, Hayley C. Whitaker, Mark J. Dunning, Alastair D. Lamb, Antonio Ramos-Montoya, Daniel S. Brewer, Colin S. Cooper, Rosalind Eeles, Anne Y. Warren, Simon Tavaré, David E. Neal, Andy G. Lynch, UK Prostate ICGC Group

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

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 multifocal 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 languageEnglish
Pages (from-to)131-144
Number of pages14
JournalEndocrine-Related Cancer
Volume22
Issue number2
DOIs
Publication statusPublished - 1 Apr 2015

Keywords

  • AR
  • Epigenetics
  • ERG
  • HES5
  • HES6
  • Methylation
  • NOTCH
  • Prostate cancer

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