| Targeting the histone reader ZMYND8 inhibits antiandrogen-induced neuroendocrine tumor transdifferentiation of prostate cancer | |
| 论文作者 | Wang, HL; Zhang, SL; Pan, Q; Guo, JC; Li, N; Chen, LF; Xu, JY; Zhou, JY; Gu, YQ; Wang, XG; Zhang, GY; Lian, YN; Zhang, W; Lin, NH; Jin, ZG; Zang, Y; Lan, WH; Cheng, XY; Tan, MJ; Chen, FX; Jiang, J; Liu, QL; Zheng, MY; Qin, J |
| 期刊/会议名称 | NATURE CANCER |
| 论文年度 | 2025 |
| 论文类别 | |
| 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. |
| 卷 | 6 |
| 影响因子 | 28.5 |
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