HES5 silencing is an early and recurrent change in prostate tumourigenesis
MetadataShow full item record
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.
Massie , C E , Spiteri , I , Ross-Adams , H , Luxton , H , Kay , J , Whitaker , H C , Dunning , M J , Lamb , A D , Ramos-Montoya , A , Brewer , D S , Cooper , C S , Eeles , R , Warren , A Y , Tavaré , S , Neal , D E , Lynch , A G & UK Prostate ICGC Group 2015 , ' HES5 silencing is an early and recurrent change in prostate tumourigenesis ' Endocrine-Related Cancer , vol 22 , no. 2 , pp. 131-144 . DOI: 10.1530/ERC-14-0454
© 2015 The authors. Published by Bioscientifica Ltd. This work is licensed under a Creative Commons Attribution 3.0 Unported License.
The ICGC Prostate UK Group is funded by Cancer Research UK Grant C5047/A14835, by the Dallaglio Foundation, and by The Wellcome Trust. The Human Research Tissue Bank is supported by the NIHR Cambridge Biomedical Research Centre.
Items in the St Andrews Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.