FOXA2 and NKX2-1 Orchestrate Neuroendocrine Lineage Plasticity in Prostate Cancer

Neuroendocrine prostate cancer (NEPC) is a treatment-resistant subtype that arises through lineage plasticity, allowing tumor cells to bypass androgen receptor (AR)–targeted therapies. In a recent study, Lu et al. define a transcriptional and epigenetic hierarchy that drives this transdifferentiation. The pioneer factor FOXA2 initiates enhancer remodeling and regional DNA demethylation, while the neural lineage transcription factor NKX2-1 is required to complete the NE program. Together, these factors reorganize 3D chromatin architecture and activate lineage-specific genes through enhancer–promoter looping. Crucially, the histone acetyltransferase p300/CBP is essential cofactor in this process. Pharmacologic inhibition of p300/CBP with CCS1477 suppresses NE gene expression and impairs tumor growth in NEPC models. These findings offer a mechanistic insight of lineage plasticity and highlight p300/CBP as promising therapeutic targets. The study also raises key questions about the stability and reversibility of chromatin remodeling and sets a framework for understanding enhancer-driven plasticity in other cancers.