Lu Xiaodong, Keo Viriya, Cheng Irina, Xie Wanqing, Gritsina Galina, Wang Juan, Lu Lina, Shiau Cheng-Kai, He Yueying, Jin Qiushi, Jin Peng, Sanda Martin G, Corces Victor G, Altemose Nicolas, Gao Ruli, Zhao Jonathan C, Yu Jindan
Department of Urology, Emory University School of Medicine, Atlanta, GA, USA.
Division of Hematology and Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Nat Genet. 2025 Jul 21. doi: 10.1038/s41588-025-02265-4.
A substantial amount of castration-resistant prostate cancer (CRPC) progresses into a neuroendocrine (NE) subtype, known as NEPC, which is associated with poor clinical outcomes. Here we report distinct three-dimensional chromatin architectures between NEPC and CRPC tumors, which were recapitulated by isogenic cell lines undergoing NE transformation (NET). Mechanistically, pioneer factors such as FOXA2 initiate binding at NE enhancers to mediate regional DNA demethylation and induce neural transcription factor (TF) NKX2-1 expression. NKX2-1 preferentially binds gene promoters and interacts with enhancer-bound FOXA2 through chromatin looping. NKX2-1 is highly expressed in NEPC and indispensable for NET of prostate cancer. NKX2-1/FOXA2 further recruits p300/CBP to activate NE enhancers, and pharmacological inhibition of p300/CBP effectively blunts NE gene expression and abolishes NEPC tumor growth. Taken together, our study reports a hierarchical network of TFs governed by NKX2-1 in critically regulating chromatin remodeling and driving luminal-to-NE transformation and suggests promising therapeutic approaches to mitigate NEPC.
大量去势抵抗性前列腺癌（CRPC）会进展为神经内分泌（NE）亚型，即神经内分泌前列腺癌（NEPC），其与不良临床预后相关。在此，我们报告了NEPC和CRPC肿瘤之间不同的三维染色质结构，等基因细胞系经NE转化（NET）后可重现这些结构。从机制上讲，先锋因子如FOXA2在NE增强子处起始结合，介导局部DNA去甲基化并诱导神经转录因子（TF）NKX2-1表达。NKX2-1优先结合基因启动子，并通过染色质环化与结合在增强子上的FOXA2相互作用。NKX2-1在NEPC中高表达，且对前列腺癌的NET不可或缺。NKX2-1/FOXA2进一步招募p300/CBP以激活NE增强子，对p300/CBP的药理学抑制可有效抑制NE基因表达并消除NEPC肿瘤生长。综上所述，我们的研究报告了一个由NKX2-1调控的转录因子层次网络，其在关键调控染色质重塑以及驱动管腔型向NE转化中发挥作用，并提出了减轻NEPC的有前景的治疗方法。
