ETV5 accelerates therapy-induced neuroendocrine prostate cancer development by inducing neural stem-like cell differentiation [RNA-seq]

Neuroendocrine prostate cancer (NEPC) is an aggressive subtype induced by hormone therapy, presenting significant therapeutic challenges due to the lack of effective treatments. In this study, we explored the role of ETV5 in NEPC development. Analysis of multiple prostate cancer datasets revealed significantly elevated ETV5 expression in NEPC compared to other subtypes. ETV5 expression increased progressively under hormone therapy conditions through epigenetic modifications. ETV5 overexpression induced NEPC-like features in LNCaP cells and facilitated their differentiation into NEPC under hormone treatment conditions, both in vitro and in vivo. Our molecular mechanism study identified PBX3 and TLL1 as ETV5 target genes, contributing to castration resistance and stemness induced by ETV5 overexpression. Notably, obeticholic acid, identified as an ETV5 inhibitor in this study, exhibited promising efficacy in suppressing NEPC development. This study highlights ETV5 as a key transcription factor driving NEPC development and underscores its potential as a therapeutic target for this aggressive cancer subtype.