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

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.