Targeting the histone reader ZMYND8 inhibits antiandrogen-induced neuroendocrine tumor transdifferentiation of prostate cancer
文献类型：期刊论文
| 作者 | Wang, Hanling1; Zhang, Sulin5; Pan, Qiang1,4; Guo, Jiacheng1; Li, Ni1,4; Chen, Lifan5; Xu, Junyu5; Zhou, Jingyi5; Gu, Yongqiang1; Wang, Xuege1 |
| 刊名 | NATURE CANCER
 |
| 出版日期 | 2025-03-18 |
| 页码 | 37 |
| DOI | 10.1038/s43018-025-00928-z |
| 通讯作者 | Liu, Qiuli(liuqiuli900827@163.com) ; Zheng, Mingyue(myzheng@simm.ac.cn) ; Qin, Jun(qinjun@sibs.ac.cn) |
| 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. |
| WOS关键词 | LINEAGE PLASTICITY ; MOUSE MODEL ; RESISTANCE ; TRANSCRIPTION ; METASTASIS ; DIFFERENTIATION ; IDENTIFICATION ; SUPPRESSION ; ACTIVATION ; MECHANISMS |
| 资助项目 | National Natural Science Foundation of China (National Science Foundation of China)[2021YFA1300601] ; National Natural Science Foundation of China (National Science Foundation of China)[2018YFA0902700] ; National Natural Science Foundation of China (National Science Foundation of China)[2022YFC3400504] ; National Key Research and Development Program of China[82425103] ; National Key Research and Development Program of China[82341012] ; National Key Research and Development Program of China[81825018] ; National Key Research and Development Program of China[82130085] ; National Key Research and Development Program of China[82203495] ; National Key Research and Development Program of China[T2225002] ; National Key Research and Development Program of China[82372771] ; National Natural Science Foundation of China Projects[JCYJ-SHFY-2022-007] ; Shanghai Pilot Program for Basic Research CAS ; Innovative Research Team of High-Level Local Universities in Shanghai[2023288] ; Innovative Research Team of High-Level Local Universities in Shanghai[2023296] ; Youth Innovation Promotion Association of the CAS[BX20240398] ; Youth Innovation Promotion Association of the CAS[2023716] ; Postdoctoral Innovation Talents support program |
| WOS研究方向 | Oncology |
| 语种 | 英语 |
| WOS记录号 | WOS:001447358700001 |
| 出版者 | NATURE PORTFOLIO |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/316686]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Liu, Qiuli; Zheng, Mingyue; Qin, Jun |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Nutr & Hlth, CAS Key Lab Tissue Microenvironm & Tumor, Shanghai, Peoples R China 2.Fudan Univ, Fudan Univ Shanghai Canc Ctr, Inst Biomed Sci, Shanghai Key Lab Med Epigenet,Minist Sci & Techno, Shanghai, Peoples R China 3.Army Med Univ, Daping Hosp, Dept Urol, Chongqing, Peoples R China 4.Jinfeng Lab, Chongqing, Peoples R China 5.Chinese Acad Sci, Univ Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr,State Key Lab Drug Re, Shanghai, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wang, Hanling,Zhang, Sulin,Pan, Qiang,et al. Targeting the histone reader ZMYND8 inhibits antiandrogen-induced neuroendocrine tumor transdifferentiation of prostate cancer[J]. NATURE CANCER,2025:37. |
| APA | Wang, Hanling.,Zhang, Sulin.,Pan, Qiang.,Guo, Jiacheng.,Li, Ni.,...&Qin, Jun.(2025).Targeting the histone reader ZMYND8 inhibits antiandrogen-induced neuroendocrine tumor transdifferentiation of prostate cancer.NATURE CANCER,37. |
| MLA | Wang, Hanling,et al."Targeting the histone reader ZMYND8 inhibits antiandrogen-induced neuroendocrine tumor transdifferentiation of prostate cancer".NATURE CANCER (2025):37. |
入库方式： OAI收割
来源：上海药物研究所
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