Hes6 expression is controlled by c-Myc and the AR to promote E2F1 activity and poor outcome in castrate-resistant prostate cancer (LNCaP)

Hes6 is a transcription co-factor that is associated with stem cell characteristics in neural tissue, but its role in cancer remains uncertain. Here we show that Hes6 is controlled by c-Myc and the AR and can drive castration resistance in xenografts of the androgen-dependent LNCaP prostate cancer cell line model. Hes6 activates a cell cycle enhancing transcriptional network that maintains tumour growth in the absence of circulating androgen but with maintained nuclear AR. We demonstrate interaction between E2F1, the AR and Hes6 and show the co-dependency of these factors in the castration-resistant setting. In the clinical setting, we have discovered a Hes6-associated signature that predicts poor outcome in prostate cancer, which could be pharmacologically targeted.

6

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