Hes6 drives a critical AR transcriptional program to induce castration resistant prostate cancer through activation of an E2F1-mediated cell cycle network. Homo sapiens

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. 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 other transcription factors including E2F1. In the clinical setting, we have uncovered a Hes6-associated signature that predicts poor outcome in prostate cancer, which can be pharmacologically targeted with restoration of sensitivity to castration. Overall design: AR and E2F1 ChIPseq from multiple simultaneous LNCaP cell replicates with and without bicalutamide