Neuroendocrine
prostate cancer (NEPC) is a lethal subtype of
prostate cancer. It is characterized by the loss of
androgen receptor (AR) signaling in neuroendocrine transdifferentiation, and finally, resistance to AR-targeted
therapy. With the application of a new generation of potent AR inhibitors, the incidence of NEPC is gradually increasing. The molecular mechanism of neuroendocrine differentiation (NED) after
androgen deprivation
therapy (ADT) remains largely unclear. In this study, using NEPC-related genome sequencing database analyses, we screened RACGAP1, a common differentially expressed gene. We investigated RACGAP1 expression in clinical
prostate cancer specimens by IHC. Regulated pathways were examined by Western blotting, qRT-PCR,
luciferase reporter,
chromatin immunoprecipitation, and immunoprecipitation assays. The corresponding function of RACGAP1 in
prostate cancer was analyzed by
CCK-8 and Transwell assays. The changes of neuroendocrine markers and AR expression in C4-2-R and C4-2B-R cells were detected in vitro. We confirmed that RACGAP1 contributed to NE transdifferentiation of
prostate cancer. Patients with high
tumor RACGAP1 expression had shorter relapse-free survival time. The expression of RACGAP1 was induced by E2F1. RACGAP1 promoted neuroendocrine transdifferentiation of
prostate cancer by stabilizing EZH2 expression in the
ubiquitin-
proteasome pathway. Moreover, overexpression of RACGAP1 promoted
enzalutamide resistance of
castration-resistant
prostate cancer (CRPC) cells. Our results showed that the upregulation of RACGAP1 by E2F1 increased EZH2 expression, which drove NEPC progression. This study explored the molecular mechanism of NED and may provide novel methods and ideas for targeted
therapy of NEPC.