Hes6 drives a network with therapeutic potential in castrate-resistant prostate cancer

Castrate-resistant prostate cancer (CRPC) is poorly characterized and heterogeneous and while the androgen receptor (AR) is of singular importance in early prostate cancer, other factors such as c-Myc and the E2F family also play a role in later stage disease. Hes6 is a transcription co-factor that has been associated with neurogenesis during gastrulation, a neuroendocrine phenotype in the prostate and metastasis in breast cancer but its role in prostate cancer remains uncertain. Here we show that Hes6 is controlled by c-Myc and AR and drives castration resistance in prostate cancer. Hes6 activates a cell-cycle enhancing transcriptional network that maintains tumour growth and nuclear AR localization in castrate conditions. We show aphysical interaction between E2F1 and both Hes6 and AR, and suggest a co-dependency of these transcription factors in castration-resistance. In the clinical setting, we have uncovered a Hes6-associated signature that predicts poor outcome in prostate cancer, which can be pharmacologically targeted. 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.

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Ramos-Montoya A, Lamb AD, Russell R, Carroll T, Jurmeister S, Galeano-Dalmau N, Massie CE, Boren J, Bon H, Theodorou V, Vias M, Shaw GL, Sharma NL, Ross-Adams H, Scott HE, Vowler SL, Howat WJ, Warren AY, Wooster RF, Mills IG, Neal DE