FOXA2 and ASCL1 Cooperate in Driving Neuronal Lineage Commitment in Prostate Cancer [ChIP-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: Chromatin Immunoprecipitation DNA sequencing (ChIPseq) for FOXA2 in NCI-H660.

在去势抵抗性前列腺癌（castration-resistant prostate cancer）中，谱系可塑性介导了对雄激素受体通路抑制剂（androgen receptor pathway inhibitors, ARPIs）的耐药性，并促使腺癌向神经内分泌前列腺癌（neuroendocrine prostate cancer, NEPC）进展——后者是一类侵袭性极强且机制尚不明确的亚型。ASCL1已被确立为NEPC表型的核心调控因子，可驱动神经内分泌分化。然而，ASCL1对神经元谱系转换与成熟的调控作用，以及其在NEPC中的互作伙伴，目前仍知之甚少。本研究解析了ARPI诱导的NEPC与终末期NEPC中ASCL1的顺式调控组（cistrome）重编程过程，发现ASCL1的结合模式可调控后续转录因子组合的表达，而这些转录因子组合是不同终末期NEPC特征的基础。我们鉴定出FOXA2是终末期NEPC中ASCL1的主要辅因子，其在ASCL1驱动的NEPC中呈高表达状态。FOXA2与ASCL1相互作用并协同调控前列腺癌中的终末神经元分化，同时调控包括PROX1在内的关键神经内分泌相关基因。本研究揭示了不同谱系决定性转录因子之间相互作用的分子通路，为维持前列腺癌的神经内分泌表型提供了理论依据。整体实验设计：针对NCI-H660细胞中的FOXA2开展染色质免疫沉淀测序（Chromatin Immunoprecipitation DNA sequencing, ChIP-seq）。