We then characterise an interaction between the epigenetic silencing of HES5 and the expression of HES6 and provide evidence for interactions with known oncogenic pathways in prostate cancer (namely AR signalling and ERG gene fusions), highlighting a transcriptional network that is altered in prostate cancer development first by an epigenetic change and then by a genomic rearrangement. Here, HES6 is linked to Familial prostate cancer.