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


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Authors

Massie, Charles E 
Spiteri, Inmaculada 
Ross-Adams, Helen 
Luxton, Hayley 
Kay, Jonathan 

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.

Description

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

Journal Title

Endocr Relat Cancer

Conference Name

Journal ISSN

1351-0088
1479-6821

Volume Title

Publisher

Bioscientifica
Sponsorship
Prostate Cancer UK (PA14-022)
Cancer Research UK (via Institute of Cancer Research (ICR)) (C5047/A14835)
Cancer Research UK (20406)
The authors are grateful to study volunteers for their participation and staff at the Welcome Trust Clinical Research Facility, Addenbrooke’s Clinical Research Centre, Cambridge. They also thank the NIHR Cambridge Biomedical Research Centre, the DOH HTA (ProtecT grant), and the NCRI/MRC (ProMPT grant) for help with the bio-repository, The University of Cambridge, Hutchison Whampoa Limited and Cancer Research UK for funding. They are grateful to the CRUK Cambridge Institute Genomics and Bioinformatics Core Facilities. Cross-validation of HES5 methylation includes the use of data generated by the TCGA Research Network.