Role of Hes6 in castration-resistant prostate cancer

Abstract

BackgroundCastration-resistant prostate cancer is a heterogeneous conditon that is poorly characterised. Although the androgen receptor (AR) is of particular importance, other factors such as c-Myc and the E2F family also have a role in later stage disease. Hes6 is a transcription cofactor associated with stem-cell characteristics in neural tissue, but its role in cancer remains uncertain. We aimed to assess the role of Hes6 in castration-resistant prostate cancer and to identify its prognostic and therapeutic relavance. MethodsWe transduced an androgen-sensitive cell line (LNCaP) to constitutively overexpress Hes6 and luciferase to permit xenografting in NOD-SCID gamma mice and bioluminescent monitoring of tumour growth. We used microarray genomics and chromatin immunoprecipitation-sequencing to study the molecular environment underpinning the cellular effects of Hes6. We generated a 61-patient hormone relapsed prostate cancer tissue microarray and assessed 285 publicly available human prostate cancers in a meta-analysis to profile Hes6 and its associated regulome in aggressive human disease. FindingsWe found that Hes6 was upregulated in aggressive human prostate cancer with its expression controlled by c-Myc and AR. Hes6 drove castration-resistant tumour growth by enhancing AR transcriptional activity in the absence of ligand binding. The AR was preferentially directed to a regulatory network enriched for other transcription factors including E2F1. We found a physical interaction between E2F1 and both Hes6 and AR, with increased occupancy of AR at E2F1 target sites in the presence of Hes6. In the clinical setting, we uncovered a Hes6-associated signature that predicts poor outcome in prostate cancer on longitudinal follow-up of men after prostatectomy. We found, in our model of castration resistance, that this process can be pharmacologically targeted by inhibition of PLK1, part of the Hes6 and E2F1 regulome, with restoration of sensitivity to castration. InterpretationWe have shown for the first time, to our knowledge, the crucial role of Hes6 in development of castration-resistant prostate cancer and identified its potential in patient-specific therapeutic strategies. FundingCambridge Biomedical Research Centre, GlaxoSmithKline, Raymond and Beverley Sackler Studentship.