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<p>Radioresistance remains a major barrier in esophageal squamous cell carcinoma (ESCC). This study demonstrates small nucleolar RNA <i>SNORA23</i> as a pathogenic epigenetic driver of intrinsic radioresistance, with its overexpression tightly correlating with advanced T-stage, lymph node metastasis, and adverse clinical outcomes in a chemoradiotherapy cohort. Mechanistically, <i>SNORA23</i> directly binds the ARID domain of histone demethylase KDM5C via a structurally defined G11-Ser169 interface—obstructing KDM5C chromatin binding to derepress DNA repair scaffolding gene SFPQ. This chromatin reprogramming enables SFPQ-facilitated recruitment of RAD51 and Ku80 to DNA double-strand breaks, accelerating homologous recombination (HR) and non-homologous end joining (NHEJ). SFPQ high expression recapitulates <i>SNORA23</i>-mediated repair enhancement and reduced radiosensitivity. Therapeutically, <i>SNORA23</i>-targeting antisense oligonucleotides (ASOs) disrupt this axis, impair DNA repair, and synergize with radiotherapy to suppress tumor growth and prolong survival in vivo without evident systemic toxicity These findings define a snoRNA–chromatin–repair axis driving therapeutic resistance and support <i>SNORA23</i> inhibition as a promising strategy to overcome radioresistance in ESCC.</p>

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SNORA23-KDM5C epigenetic axis mediates dual DNA repair pathways to drive radioresistance in esophageal squamous cell carcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月14日

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  • Baoqing Tian,
  • Hua Zhang,
  • Jiao Ren,
  • Jupeng Yuan,
  • Songyue Guo,
  • Yue Shen,
  • Xinyi Huang,
  • Zengfu Zhang,
  • Xianrui Shan,
  • Yongchun Xie,
  • Fei Wang,
  • Ying Xu,
  • Jiayi Liu,
  • Meng Wu,
  • Jinming Yu,
  • Dawei Chen

摘要

Radioresistance remains a major barrier in esophageal squamous cell carcinoma (ESCC). This study demonstrates small nucleolar RNA SNORA23 as a pathogenic epigenetic driver of intrinsic radioresistance, with its overexpression tightly correlating with advanced T-stage, lymph node metastasis, and adverse clinical outcomes in a chemoradiotherapy cohort. Mechanistically, SNORA23 directly binds the ARID domain of histone demethylase KDM5C via a structurally defined G11-Ser169 interface—obstructing KDM5C chromatin binding to derepress DNA repair scaffolding gene SFPQ. This chromatin reprogramming enables SFPQ-facilitated recruitment of RAD51 and Ku80 to DNA double-strand breaks, accelerating homologous recombination (HR) and non-homologous end joining (NHEJ). SFPQ high expression recapitulates SNORA23-mediated repair enhancement and reduced radiosensitivity. Therapeutically, SNORA23-targeting antisense oligonucleotides (ASOs) disrupt this axis, impair DNA repair, and synergize with radiotherapy to suppress tumor growth and prolong survival in vivo without evident systemic toxicity These findings define a snoRNA–chromatin–repair axis driving therapeutic resistance and support SNORA23 inhibition as a promising strategy to overcome radioresistance in ESCC.