Abstract
Neuroendocrine prostate cancer (NEPC) is the most lethal malignancy of prostate cancer (PCa). Treatment with next-generation androgen receptor (AR) pathway inhibitors (ARPIs) has successfully extended patients' lifespan. However, with the emergence of drug resistance, PCa tumors increasingly adapt to potent ARPI therapies by transitioning to alternative cellular lineage. Such therapy-induced drug resistance is largely driven from the cellular plasticity of PCa cells to alter their phenotypes of AR independence for cell growth and survival. Some of the resistant PCa cells undergo cellular reprogramming to form neuroendocrine phenotypes. Recent evidences suggest that this cellular reprogramming or the lineage plasticity is driven by dysregulation of the epigenome and transcriptional networks. Aberrant DNA methylation and altered expression of epigenetic modifiers, such as enhancer of zeste-homolog 2, transcription factors, histone demethylases, are hallmarks of NEPC. In this review, we discuss the nature of the epigenetic and transcriptional landscapes of PCa cells which lose their AR independence and transition to the neuroendocrine lineage. We also discuss how oncogenic signaling and metabolic reprogramming fuel epigenetic and transcriptional alterations. In addition, the current state of epigenetic therapies for NEPC is addressed.