FOXA2 and ASCL1 Cooperate in Driving Neuronal Lineage Commitment in Prostate Cancer [RNA-seq]
In castration-resistant prostate cancer, lineage plasticity mediates resistance to androgen receptor pathway inhibitors (ARPIs) and progression from adenocarcinoma to neuroendocrine prostate cancer (NEPC), a highly aggressive and poorly understood subtype. ASCL1 has emerged as a central regulator of the NEPC phenotype, driving neuroendocrine differentiation. However, ASCL1's influence on neuronal lineage switching and maturation, as well as its partners in NEPC, remain largely unknown. Here, we provided insights into ASCL1's cistrome reprogramming in ARPI-induced NEPC versus terminal NEPC and showed that ASCL1 binding pattern tailors the subsequent expression of transcription factor combinations that underlie discrete terminal NEPC identity. We identified FOXA2 as a major co-factor of ASCL1 in terminal NEPC that it is highly expressed  in ASCL1-driven NEPC. FOXA2 and ASCL1  interact and work in concert to orchestrate terminal neuronal differentiation in prostate cancer, and regulate key neuroendocrine-associated genes including PROX1. Our findings provide insights into the molecular conduit underlying the interplay between different lineage determinant transcription factors to support the neuroendocrine identity in prostate cancer. Overall design: To investigate the role of FOXA2 in Neuro endocrine prostate cancer, FOXA2 gene was knocked out using shRNA in NCI-H660 cell line and gene expression analysis was performed using RNAseq data from two biological replicates.