Scholarlink

<p>Temozolomide is a standard-of-care therapeutic agent for glioblastoma. However, persons who initially respond well often experience a notable reduction in efficacy over time, with the underlying mechanisms remaining unclear. Here we demonstrate that the reduced response to temozolomide correlates with decreased chromatin accessibility, marked by reduced H3K27ac modification and alterations in chromatin loops. Mechanistically, temozolomide treatment upregulates histone deacetylase 1 (HDAC1) expression. Intriguingly, increased HDAC1 forms condensates independently of its deacetylase function. These condensates arise from multivalent interactions within the intrinsically disordered region and specific interactions with CCCTC-binding factor (CTCF), facilitating resistance to temozolomide by promoting the assembly of DNA repair complexes, even in the absence of direct deacetylase activity of HDAC1. Through phase-separation-based screening, we identified resminostat as an effective disruptor of HDAC1–CTCF condensates, thereby restoring temozolomide sensitivity in patient-derived xenograft models. Our findings introduce deacetylase-independent HDAC1 condensation as a distinct mechanism regulating temozolomide response, providing valuable insights into potential therapeutic strategies.</p><p></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

Deacetylase-independent HDAC1 condensation defines temozolomide response in glioblastoma

  • 期刊论文

  • 发表日期：

    2026年1月9日

查看全文
  • Qinkai Zhang,
  • Ru Qiu,
  • Bing Lu,
  • Jinhong Wang,
  • Jizhao Cao,
  • Hongni Zhu,
  • Meng Huang,
  • Wenyong Long,
  • Ke Fang,
  • Chuanxia Zhang,
  • Fuxi Li,
  • Wei Shi,
  • Qing Liu,
  • Yiming Li,
  • Peng Dong,
  • Wei Zhao

摘要

Temozolomide is a standard-of-care therapeutic agent for glioblastoma. However, persons who initially respond well often experience a notable reduction in efficacy over time, with the underlying mechanisms remaining unclear. Here we demonstrate that the reduced response to temozolomide correlates with decreased chromatin accessibility, marked by reduced H3K27ac modification and alterations in chromatin loops. Mechanistically, temozolomide treatment upregulates histone deacetylase 1 (HDAC1) expression. Intriguingly, increased HDAC1 forms condensates independently of its deacetylase function. These condensates arise from multivalent interactions within the intrinsically disordered region and specific interactions with CCCTC-binding factor (CTCF), facilitating resistance to temozolomide by promoting the assembly of DNA repair complexes, even in the absence of direct deacetylase activity of HDAC1. Through phase-separation-based screening, we identified resminostat as an effective disruptor of HDAC1–CTCF condensates, thereby restoring temozolomide sensitivity in patient-derived xenograft models. Our findings introduce deacetylase-independent HDAC1 condensation as a distinct mechanism regulating temozolomide response, providing valuable insights into potential therapeutic strategies.