Scholarlink

<p>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 <i>Zmynd8</i> 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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 发表日期：

    2025年3月18日

查看全文
  • Hanling Wang,
  • Sulin Zhang,
  • Qiang Pan,
  • Jiacheng Guo,
  • Ni Li,
  • Lifan Chen,
  • Junyu Xu,
  • Jingyi Zhou,
  • Yongqiang Gu,
  • Xuege Wang,
  • Guoying Zhang,
  • Yannan Lian,
  • Wei Zhang,
  • Naiheng Lin,
  • Zige Jin,
  • Yi Zang,
  • Weihua Lan,
  • Xiaoyan Cheng,
  • Minjia Tan,
  • Fei Xavier Chen,
  • Jun Jiang,
  • Qiuli Liu,
  • Mingyue Zheng,
  • Jun Qin

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.