Epigenetic regulation of neuroendocrine prostate cancer

Neuroendocrine prostate cancer (PCa), an aggressive subtype of PCa, can arise de novo or from pre-existing castration-resistant PCa, especially after treatment with new-generation androgen receptor signaling inhibitors (ARSIs); thus, it is a major cause of resistance to ARSIs. Lineage plasticity drives the transformation of adenocarcinoma cells from the androgen receptor-driven luminal cell program to an alternative neuroendocrine transdifferentiation phenotype, which has been recognized as a key mechanism in neuroendocrine PCa development. Although genetic alterations can promote lineage plasticity, this process is primarily orchestrated through epigenetic regulation, including DNA methylation, chromatin modifications, and long noncoding RNA. Notably, epigenetic regulators are amenable therapeutic targets, offering the potential not only to address lineage plasticity but, more crucially, also to overcome resistance to ARSIs in PCa. In this review, we aim to elucidate the pivotal epigenetic factors driving the plasticity of the PCa lineage, providing a foundation for the development of treatment strategies to effectively combat resistance to ARSIs driven by lineage plasticity.