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
  • 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. [email protected].
  • 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. [email protected].
  • 8. CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 9. Jinfeng Laboratory, Chongqing, China. [email protected].
  • # 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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