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<p>Chemoradiotherapy resistance remains a major obstacle in gastric cancer treatment, primarily due to enhanced DNA repair mechanisms that allow tumor cells to overcome therapeutic damage. Here, we demonstrate that nuclear-localized Exocyst Complex Component 4 (EXOC4) promotes chemoradiotherapy resistance in gastric cancer by enhancing non-homologous end joining-mediated DNA repair. Specifically, p300-mediated acetylation of EXOC4 at lysine 433 induces its nuclear translocation. In the nucleus, EXOC4 facilitates the interaction between PRMT5 and KU70, inducing PRMT5-catalyzed methylation of KU70 at arginine 318. This modification increases the DNA-binding affinity of the KU complex, thereby accelerating double-strand break repair. A peptide targeting EXOC4 K433 inhibits acetylation-dependent nuclear import, reducing KU70 methylation and restoring chemoradiotherapy sensitivity in preclinical models. Collectively, our findings identify the p300–EXOC4–KU70 axis as a critical mediator of chemoradiotherapy resistance and a promising therapeutic target.</p><p></p>

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Acetylation-dependent nuclear translocation of EXOC4 regulates KU70 methylation to facilitate non-homologous end joining

  • 期刊论文

  • 发表日期：

    2026年3月14日

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  • Haojie Li,
  • Haoyu Sun,
  • Xu Yang,
  • Wenchao Jiang,
  • Xinyou Liu,
  • Bosen Li,
  • Chenyu Tian,
  • Junjie Zhao,
  • Yuanyuan Ruan,
  • Jie Sun,
  • Xuefei Wang

摘要

Chemoradiotherapy resistance remains a major obstacle in gastric cancer treatment, primarily due to enhanced DNA repair mechanisms that allow tumor cells to overcome therapeutic damage. Here, we demonstrate that nuclear-localized Exocyst Complex Component 4 (EXOC4) promotes chemoradiotherapy resistance in gastric cancer by enhancing non-homologous end joining-mediated DNA repair. Specifically, p300-mediated acetylation of EXOC4 at lysine 433 induces its nuclear translocation. In the nucleus, EXOC4 facilitates the interaction between PRMT5 and KU70, inducing PRMT5-catalyzed methylation of KU70 at arginine 318. This modification increases the DNA-binding affinity of the KU complex, thereby accelerating double-strand break repair. A peptide targeting EXOC4 K433 inhibits acetylation-dependent nuclear import, reducing KU70 methylation and restoring chemoradiotherapy sensitivity in preclinical models. Collectively, our findings identify the p300–EXOC4–KU70 axis as a critical mediator of chemoradiotherapy resistance and a promising therapeutic target.