Journal Article

HES6 drives a critical AR transcriptional programme to induce castration‐resistant prostate cancer through activation of an E 2 F 1‐mediated cell cycle network

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

2014

Overview

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 E 2 F 1. 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. image 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 H ES6‐responsive gene PLK 1 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 PLK 1 is highly expressed in a new hormone relapse TMA . Inhibition of PLK 1 enhances sensitivity to anti‐androgens.

• Publisher: EMBO Press
• Subject: Androgen receptors / Androgens / Biomedical research / Castration / Cell cycle / E2F1 protein / Endocrine therapy / Kinases / Medical research / Metastasis / Myc protein / Neural stem cells / Polo-like kinase 1 / Prostate cancer / Research centers / Transcription factors / Tumors