2. Academic Validation
  3. Targeting the histone reader ZMYND8 inhibits antiandrogen-induced neuroendocrine tumor transdifferentiation of prostate cancer

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

  • Nat Cancer. 2025 Apr;6(4):629-646. doi: 10.1038/s43018-025-00928-z.
Hanling Wang # 1,  Sulin Zhang # 2,  Qiang Pan # 1 3,  Jiacheng Guo 1,  Ni Li 1 3,  Lifan Chen 2,  Junyu Xu 2,  Jingyi Zhou 2,  Yongqiang Gu 1,  Xuege Wang 1,  Guoying Zhang 1,  Yannan Lian 1,  Wei Zhang 1,  Naiheng Lin 1,  Zige Jin 1,  Yi Zang 1,  Weihua Lan 4,  Xiaoyan Cheng 3,  Minjia Tan 2,  Fei Xavier Chen 5,  Jun Jiang 4,  Qiuli Liu 6,  Mingyue Zheng 7,  Jun Qin 8 9
Affiliations

Affiliations

  • 1 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China.
  • 2 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.
  • 3 Jinfeng Laboratory, Chongqing, China.
  • 4 Department of Urology, Daping Hospital, Army Medical University, Chongqing, China.
  • 5 Fudan University Shanghai Cancer Center, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
  • 6 Department of Urology, Daping Hospital, Army Medical University, Chongqing, China. liuqiuli900827@163.com.
  • 7 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. myzheng@simm.ac.cn.
  • 8 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China. qinjun@sibs.ac.cn.
  • 9 Jinfeng Laboratory, Chongqing, China. qinjun@sibs.ac.cn.
  • # Contributed equally.
PMID: 40102673 DOI: 10.1038/s43018-025-00928-z
Abstract

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.

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