美国埃默里大学医学院Jindan Yu研究团队宣布他们开发出NKX2-1通过表观遗传和三维染色质重塑驱动前列腺癌的神经内分泌转分化。相关论文于2025年7月21日发表在《自然—遗传学》杂志上。

在这里，课题组研究人员报道了NEPC和CRPC肿瘤之间不同的三维染色质结构，这些结构通过进行NE转化（NET）的等基因细胞系再现。在机制上，FOXA2等先锋因子启动NE增强子的结合，介导区域DNA去甲基化并诱导神经转录因子（TF） NKX2-1的表达。NKX2-1优先结合基因启动子，并通过染色质环与增强子结合的FOXA2相互作用。NKX2-1在NEPC中高表达，是前列腺癌NET的重要组成部分。NKX2-1/FOXA2进一步招募p300/CBP激活NE增强子，药理抑制p300/CBP可有效抑制NE基因表达，消除NEPC肿瘤生长。综上所述，他们的研究报告了一个由NKX2-1控制的tf分层网络，该网络在严格调节染色质重塑和驱动光向NE转化方面发挥着重要作用，并提出了缓解NEPC的有希望的治疗方法。

研究人员表示，大量去势抵抗性前列腺癌（CRPC）进展为神经内分泌（NE）亚型，称为NEPC，与较差的临床结果相关。

附：英文原文

Title: NKX2-1 drives neuroendocrine transdifferentiation of prostate cancer via epigenetic and 3D chromatin remodeling

Author: 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

Issue&Volume: 2025-07-21

Abstract: 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.

DOI: 10.1038/s41588-025-02265-4

Source: https://www.nature.com/articles/s41588-025-02265-4