ASCL1 activates neuronal stem cell-like lineage programing through remodeling of the chromatin landscape in prostate cancer [ATAC-Seq]

Treatment with androgen receptor pathway inhibitors (ARPIs) in prostate cancer leads to the emergence of resistant tumors characterized by lineage plasticity and divergent differentiation toward neuroendocrine lineage. We found that ARPIs induce a rapid epigenetic alteration mediated by large-scale chromatin remodeling to support activation of stem/neuronal transcriptional programs. We identified motifs for the proneuronal transcription factor ASCL1 to be enriched in hyper-accessible regions. ASCL1 acts as a driver of the lineage plastic, neuronal transcriptional program to support treatment resistance and neuroendocrine phenotype. Targeting ASCL1 switches the neuroendocrine lineage back to the luminal epithelial state. This effect is modulated by disruption of the polycomb repressive complex-2 and change the chromatin architecture in favor of luminal phenotype. Our study provides insights into the epigenetic alterations induced by ARPI governed by ASCL1, provides a proof of principle of targeting ASCL1 to reverse the neuroendocrine phenotype, support luminal conversion and re-addiction to ARPIs. Deciphering enzalutamide dependent prostate cancer stage specific chromatin accessibility profile.