Back to Search Start Over

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

Authors :
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 Mills
David E Neal
Source :
EMBO Molecular Medicine, Vol 6, Iss 5, Pp 651-661 (2014)
Publication Year :
2014
Publisher :
Springer Nature, 2014.

Abstract

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.

Details

Language :
English
ISSN :
17574676 and 17574684
Volume :
6
Issue :
5
Database :
Directory of Open Access Journals
Journal :
EMBO Molecular Medicine
Publication Type :
Academic Journal
Accession number :
edsdoj.381e788e932488b8fe13b0d3eb31910
Document Type :
article
Full Text :
https://doi.org/10.1002/emmm.201303581