Wang Hanling, Zhang Sulin, Pan Qiang, Guo Jiacheng, Li Ni, Chen Lifan, Xu Junyu, Zhou Jingyi, Gu Yongqiang, Wang Xuege, Zhang Guoying, Lian Yannan, Zhang Wei, Lin Naiheng, Jin Zige, Zang Yi, Lan Weihua, Cheng Xiaoyan, Tan Minjia, Chen Fei Xavier, Jiang Jun, Liu Qiuli, Zheng Mingyue, Qin Jun
CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China.
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
Nat Cancer. 2025 Apr;6(4):629-646. doi: 10.1038/s43018-025-00928-z. Epub 2025 Mar 18.
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.
男性腺癌向神经内分泌前列腺癌（NEPC）的转分化赋予了抗雄激素治疗抗性。在此，我们将CRISPR-Cas9筛选与肿瘤转变的单细胞RNA测序追踪相结合进行分析，结果表明抗雄激素诱导的含锌指MYND结构域8（ZMYND8）依赖性表观遗传编程调控着NEPC的转分化。敲除Zmynd8可阻止NEPC的发生，而由achaete-scute同源物1介导的ZMYND8上调则促进NEPC分化。我们发现叉头框蛋白M1（FOXM1）可稳定ZMYND8与以H3K4me1-H3K14ac修饰和FOXM1靶向为特征的染色质区域的结合。抗雄激素治疗使SWI/SNF染色质重塑复合物从雄激素受体上释放出来，促进其与ZMYND8-FOXM1相互作用，从而上调关键的神经内分泌谱系调节因子。我们开发了iZMYND8-34，一种旨在抑制ZMYND8组蛋白识别功能的小分子，它能有效阻断NEPC的发生。这些发现揭示了雄激素剥夺疗法诱导的ZMYND8依赖性表观遗传编程在调控谱系命运中的关键作用。靶向ZMYND8成为一种有前景的阻碍NEPC发生的策略。
