文章：

靶向组蛋白解读器ZMYND8抑制抗雄激素诱导的前列腺癌神经内分泌肿瘤转分化

Targeting the histone reader ZMYND8 inhibits antiandrogen-induced neuroendocrine tumor transdifferentiation of prostate cancer 

原文发布日期：2025-03-18 

英文摘要：

The transdifferentiation from adenocarcinoma to neuroendocrine prostate cancer (NEPC) in men confers antiandrogen therapy resistance. Here our analysis combining CRISPR‒Cas9 screening with single-cell RNA sequencing tracking of tumor transition demonstrated that antiandrogen-induced zinc finger MYND-type containing 8 (ZMYND8)-dependent epigenetic programming orchestrates NEPC transdifferentiation. Ablation of Zmynd8 prevents NEPC development, while ZMYND8 upregulation mediated by achaete-scute homolog 1 promotes NEPC differentiation. We show that forkhead box protein M1 (FOXM1) stabilizes ZMYND8 binding to chromatin regions characterized by H3K4me1–H3K14ac modification and FOXM1 targeting. Antiandrogen therapy releases the SWI/SNF chromatin remodeling complex from the androgen receptor, facilitating its interaction with ZMYND8–FOXM1 to upregulate critical neuroendocrine lineage regulators. We develop iZMYND8-34, a small molecule designed to inhibit ZMYND8’s histone recognition, which effectively blocks NEPC development. These findings reveal the critical role of ZMYND8-dependent epigenetic programming induced by androgen deprivation therapy in orchestrating lineage fate. Targeting ZMYND8 emerges as a promising strategy for impeding NEPC development. 

摘要翻译：

在男性中，腺癌向神经内分泌前列腺癌（NEPC）的转分化表现出抗雌激素治疗抵抗性。我们结合CRISPR‒Cas9基因敲除和单细胞RNA测序追踪肿瘤迁移的研究分析发现，在反雄激素诱导下含有锌指MYND型蛋白8（ZMYND8）相关的表观遗传编程调控了NEPC的转分化。去除了Zmynd8后，NEPC的形成被抑制；而通过achaete-scute homolog 1介导的ZMYND8上调促进了NEPC的分化。我们证明了Forkhead box蛋白M1（FOXM1）稳定了ZMYND8与标记为H3K4me1–H3K14ac修饰区域结合的能力，并且FOXM1靶向作用。反雄激素治疗释放了SWI/SNF染色质重塑复合体，促进其与ZMYND8-FOXM1相互作用，上调关键的神经内分泌祖细胞调节器。我们设计并合成了iZMYND8-34，这是一种小分子药物，能够抑制ZMYND8对 histone 的识别作用，从而有效阻止了NEPC的形成。这些发现揭示了依赖于雄激素剥夺治疗诱导的ZMYND8相关表观遗传编程在调控祖细胞命运中的关键作用。靶向ZMYND8是一种阻断NEPC进展的有效策略。 

原文链接：

https://www.nature.com/articles/s43018-025-00928-z