HES6 drives a critical AR transcriptional programme to induce castration-resistant prostate cancer through activation of an E2F1-mediated cell cycle network

Antonio Ramos-Montoya, Alastair D Lamb, Roslin Russell, Thomas Carroll, Sarah Jurmeister, Nuria Galeano-Dalmau, Charlie E Massie, Joan Boren, Helene Bon, Vasiliki Theodorou, Maria Vias, Greg L Shaw, Naomi L Sharma, Helen Ross-Adams, Helen E Scott, Sarah L Vowler, William J Howat, Anne Y Warren, Richard F Wooster, Ian G MillsDavid E Neal

Research output: Contribution to journalArticlepeer-review

41 Citations (Scopus)
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Abstract

Castrate-resistant prostate cancer (CRPC) is poorly characterized and heterogeneous and while the androgen receptor (AR) is of singular importance, other factors such as c-Myc and the E2F family also play a role in later stage disease. HES6 is a transcription co-factor associated with stem cell characteristics in neural tissue. Here we show that HES6 is up-regulated in aggressive human prostate cancer and drives castration-resistant tumour growth in the absence of ligand binding by enhancing the transcriptional activity of the AR, which is preferentially directed to a regulatory network enriched for transcription factors such as E2F1. In the clinical setting, we have uncovered a HES6-associated signature that predicts poor outcome in prostate cancer, which can be pharmacologically targeted by inhibition of PLK1 with restoration of sensitivity to castration. We have therefore shown for the first time the critical role of HES6 in the development of CRPC and identified its potential in patient-specific therapeutic strategies.

Original languageEnglish
Pages (from-to)651-61
Number of pages11
JournalEMBO Molecular Medicine
Volume6
Issue number5
Early online date14 Apr 2014
DOIs
Publication statusPublished - 01 May 2014

Keywords

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Cycle Proteins
  • Disease Models, Animal
  • E2F1 Transcription Factor
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Humans
  • Male
  • Mice
  • Molecular Sequence Data
  • Prostatic Neoplasms
  • Receptors, Androgen
  • Repressor Proteins
  • Sequence Analysis, DNA

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