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 ,Thomas Carroll,Sarah Jurmeister,Roslin Russell,Joan Boren,Maria Vias,Núria Galeano-Dalmau ,Anne Y Warren ,Helen E Scott ,Richard Wooster ,Hélène Bon ,Naomi L Sharma ,Vassiliki Théodorou ,Sarah L Vowler ,Greg L Shaw ,Alastair Lamb ,William J Howat ,Ian G Mills ,Helen Ross-Adams ,Charles E Massie ,David E Neal

doi:10.1002/emmm.201303581

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.

Highlights

Prostate cancer is the most common non-cutaneous malignancy in men in western countries (CRUK, 2010)
Using the androgen-dependent LNCaP cell line and chromatin immunoprecipitation sequencing (ChIPseq), we showed that two potent oncogenes in prostate cancer, the androgen receptor (AR) (Massie et al, 2011) and c-Myc, bind upstream of the HES6 coding sequence (Supplementary Fig S1A) to positively regulate levels of HES6 mRNA (Fig 1A, Supplementary Fig S1B and C) and confirmed that overexpression of c-Myc overcomes growth inhibition by bicalutamide (Bernard et al, 2003) (Supplementary Fig S1D), an effect that can be reversed by knock-down of HES6 (Supplementary Fig S1E)
We have identified HES6 as a transcription co-factor that is able to alter prostate cancer cell phenotype so fundamentally that these cells are able to grow in the absence of testosterone

Summary

Introduction

Prostate cancer is the most common non-cutaneous malignancy in men in western countries (CRUK, 2010). Several mechanisms have been proposed to explain how this aggressive phase of the disease develops. Most depend on continued androgen receptor (AR) signalling in the context of enhanced secondary pathways, while others are independent of conventional AR activity (Pienta & Smith, 2005; Lamb et al, 2014). This heterogeneity explains why, virtually all primary locally advanced prostate cancer can be treated effectively with androgen deprivation therapy (ADT), CRPC remains difficult to treat, and those therapies that have been developed are only effective for a limited duration in a limited set of patients (Yap et al, 2011).

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Results

Conclusion