In summary, our data suggest that H3.3-enriched enhancer chromatin serves as a platform for H3K27Ac-mediated BRD4 recruitment, which interacts with and retains AR at enhancer AREs, resulting in AR-driven transcription reprogramming, thus identifying H3.3 function in nuclear receptors activity and placing HIRA complex at the epicenter of H3.3 pathways in PC initiation and/or progression. This evidence concerns the gene HIRA and pachyonychia congenita.