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

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 char...

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Veröffentlicht in:	EMBO molecular medicine Jg. 6; H. 5; S. 651 - 661
Hauptverfasser:	Ramos‐Montoya, Antonio, Lamb, Alastair D, Russell, Roslin, Carroll, Thomas, Jurmeister, Sarah, Galeano‐Dalmau, Nuria, Massie, Charlie E, Boren, Joan, Bon, Helene, Theodorou, Vasiliki, Vias, Maria, Shaw, Greg L, Sharma, Naomi L, Ross‐Adams, Helen, Scott, Helen E, Vowler, Sarah L, Howat, William J, Warren, Anne Y, Wooster, Richard F, Mills, Ian G, Neal, David E
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	London Nature Publishing Group UK 01.05.2014 BlackWell Publishing Ltd Springer Nature
Schlagworte:	androgen receptor Animals Basic Helix-Loop-Helix Transcription Factors - genetics Basic Helix-Loop-Helix Transcription Factors - metabolism castrate‐resistant prostate cancer Cell Cycle Proteins - metabolism Disease Models, Animal E2F1 Transcription Factor - genetics E2F1 Transcription Factor - metabolism EMBO03 EMBO45 Gene Expression Profiling Gene Expression Regulation gene expression signature HES6 Humans Male Mice Molecular Sequence Data PLK1 Prostatic Neoplasms - pathology Prostatic Neoplasms - physiopathology Receptors, Androgen - metabolism Repressor Proteins - genetics Repressor Proteins - metabolism Research Article Sequence Analysis, DNA HES6 castrate‐resistant prostate cancer androgen receptor gene expression signature PLK1
ISSN:	1757-4676, 1757-4684, 1757-4684
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Zusammenfassung:	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. Synopsis HES6 promotes castration resistance, maintains AR chromatin binding at a subset of sites in the absence of hormone stimulation and predicts poor outcome after prostatectomy. Inhibition of HES6‐responsive gene PLK1 enhances anti‐androgen sensitivity. HES6 promotes castration resistance in prostate cancer cells. HES6 maintains AR chromatin binding at a subset of sites in the absence of hormone stimulation. HES6‐associated genes predict poor clinical outcome after radical prostatectomy. HES6‐responsive gene PLK1 is highly expressed in a new hormone relapse TMA. Inhibition of PLK1 enhances sensitivity to anti‐androgens. Graphical Abstract HES6 promotes castration resistance, maintains AR chromatin binding at a subset of sites in the absence of hormone stimulation and predicts poor outcome after prostatectomy. Inhibition of HES6‐responsive gene PLK1 enhances anti‐androgen sensitivity.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work. Subject Categories Cancer; Urogenital System Current address: Blend Therapeutics, Watertown, MA, USA Current address: Institute of Molecular Biology and Biotechnology (IMBB), Foundation for Research and Technology-Hellas (IMBB-FORTH), Heraklion, Crete, Greece Current address: Nuffield Department of Surgical Sciences, University of Oxford, Roosevelt Drive, Oxford, UK These senior authors contributed equally to this work.
ISSN:	1757-4676 1757-4684 1757-4684
DOI:	10.1002/emmm.201303581