title: HES6 drives a critical AR transcriptional programme to induce castration-resistant prostate cancer through activation of an E2F1-mediated cell cycle network.
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.
authors.affiliation: Uro-Oncology Research Group Cancer Research UK Cambridge Institute University of Cambridge Li Ka Shing Centre, Cambridge, UK.
authors.forename: Antonio
authors.initials: A
authors.lastname: Ramos-Montoya
authors.forename: Alastair D
authors.initials: AD
authors.lastname: Lamb
authors.forename: Roslin
authors.initials: R
authors.lastname: Russell
authors.forename: Thomas
authors.initials: T
authors.lastname: Carroll
authors.forename: Sarah
authors.initials: S
authors.lastname: Jurmeister
authors.forename: Nuria
authors.initials: N
authors.lastname: Galeano-Dalmau
authors.forename: Charlie E
authors.initials: CE
authors.lastname: Massie
authors.forename: Joan
authors.initials: J
authors.lastname: Boren
authors.forename: Helene
authors.initials: H
authors.lastname: Bon
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Theodorou
authors.forename: Maria
authors.initials: M
authors.lastname: Vias
authors.forename: Greg L
authors.initials: GL
authors.lastname: Shaw
authors.forename: Naomi L
authors.initials: NL
authors.lastname: Sharma
authors.forename: Helen
authors.initials: H
authors.lastname: Ross-Adams
authors.forename: Helen E
authors.initials: HE
authors.lastname: Scott
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Vowler
authors.forename: William J
authors.initials: WJ
authors.lastname: Howat
authors.forename: Anne Y
authors.initials: AY
authors.lastname: Warren
authors.forename: Richard F
authors.initials: RF
authors.lastname: Wooster
authors.forename: Ian G
authors.initials: IG
authors.lastname: Mills
authors.forename: David E
authors.initials: DE
authors.lastname: Neal
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D011471:Prostatic Neoplasms / Q000473:pathology / Q000503:physiopathology*; D011944:Receptors, Androgen / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D017422:Sequence Analysis, DNA
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D050687:E2F1 Transcription Factor; D011944:Receptors, Androgen; D012097:Repressor Proteins; C410798:AR protein, human; C493753:E2F1 protein, human; C411859:HES6 protein, human
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