HES5 silencing is an early and recurrent change in prostate tumourigenesis
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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 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.
DescriptionThe 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.
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