Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Cell Death & Differentiation (2026) Cite this article

Subjects

Abstract

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.

The alternative text for this image may have been generated using AI.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Acetylation regulates EXOC4 nuclear translocation.
The alternative text for this image may have been generated using AI.
Fig. 2: K433 acetylation drives EXOC4 nuclear translocation.
The alternative text for this image may have been generated using AI.
Fig. 3: Nuclear EXOC4 forms complexes with KU70/80 proteins.
The alternative text for this image may have been generated using AI.
Fig. 4: Nuclear EXOC4 enhances DNA repair capabilities via the NHEJ pathway.
The alternative text for this image may have been generated using AI.
Fig. 5: Nuclear EXOC4 mediates PRMT5–KU complex interactions to regulate NHEJ.
The alternative text for this image may have been generated using AI.
Fig. 6: Nuclear translocation of EXOC4 mediates KU70 R318 methylation to promote KU complex-DNA binding and enhance NHEJ repair efficiency.
The alternative text for this image may have been generated using AI.
Fig. 7: Nuclear localization of EXOC4 correlates with chemoradiotherapy response in gastric cancer.
The alternative text for this image may have been generated using AI.
Fig. 8: Inhibition of EXOC4 nuclear translocation via targeted peptides reverses chemoradiotherapy resistance in gastric cancer.
The alternative text for this image may have been generated using AI.

Similar content being viewed by others

Data availability

All data required to assess the study’s conclusions are included in this article and/or the Supplementary Materials. Any additional information relevant to the work is available from the authors upon reasonable request.

References

  1. Lin JL, Lin JX, Lin GT, Huang CM, Zheng CH, Xie JW, et al. Global incidence and mortality trends of gastric cancer and predicted mortality of gastric cancer by 2035. Bmc Public Health. 2024;24:1763.

  2. Bray F, Laversanne M, Sung HYA, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74:229–63.

    PubMed  Google Scholar 

  3. Yan XX, Lei L, Li H, Cao MM, Yang F, He SY, et al. Stomach cancer burden in China: epidemiology and prevention. Chin J Cancer Res. 2023;35:81–91.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Jiang L, Ma ZQ, Ye X, Kang WM, Yu JC. Clinicopathological factors affecting the effect of neoadjuvant chemotherapy in patients with gastric cancer. World J Surg Oncol. 2021;19:44.

  5. Eom SS, Ryu KW, Han HS, Kong SH. A comprehensive and comparative review of global gastric cancer treatment guidelines: 2024 update. J Gastric Cancer. 2025;25:153–76.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Schuhmacher C, Gretschel S, Lordick F, Reichardt P, Hohenberger W, Eisenberger CF, et al. Neoadjuvant chemotherapy compared with surgery alone for locally advanced cancer of the stomach and cardia: European organisation for research and treatment of cancer randomized trial 40954. J Clin Oncol. 2010;28:5210–8.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Paoletti X, Oba K, Burzykowski T, Michiels S, Ohashi Y, Pignon JP, et al. Benefit of adjuvant chemotherapy for resectable gastric cancer a meta-analysis. JAMA J Am Med Assoc. 2010;303:1729–37.

    Article  CAS  Google Scholar 

  8. Taniguchi K, Karin M. NF-κB, inflammation, immunity and cancer: coming of age. Nat Rev Immunol. 2018;18:309–24.

    Article  PubMed  CAS  Google Scholar 

  9. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    Article  PubMed  CAS  Google Scholar 

  10. Chatterjee N, Walker GC. Mechanisms of DNA damage, repair, and mutagenesis. Environ Mol Mutagenesis. 2017;58:235–63.

    Article  CAS  Google Scholar 

  11. Walker JR, Corpina RA, Goldberg J. Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair. Nature. 2001;412:607–14.

    Article  PubMed  CAS  Google Scholar 

  12. Pilié PG, Tang C, Mills GB, Yap TA. State-of-the-art strategies for targeting the DNA damage response in cancer. Nat Rev Clin Oncol. 2019;16:81–104.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Gullo C, Au M, Feng G, Teoh G. The biology of Ku and its potential oncogenic role in cancer. Biochim. Biophys. Acta Rev Cancer. 2006;1765:223–34.

    Article  CAS  Google Scholar 

  14. Hsu SC, TerBush D, Abraham M, Guo W. The exocyst complex in polarized exocytosis. Int Rev Cyto. 2004;233:243–65.

  15. Grindstaff KK, Yeaman C, Anandasabapathy N, Hsu SC, Rodriguez-Boulan E, Scheller RH, et al. Sec6/8 complex is recruited to cell-cell contacts and specifies transport vesicle delivery to the basal-lateral membrane in epithelial cells. Cell. 1998;93:731–40.

    Article  PubMed  CAS  Google Scholar 

  16. van Rees DJ, Bouti P, Klein B, Verkuijlen PJH, van Houdt M, Schornagel K, et al. Cancer cells resist antibody-mediated destruction by neutrophils through activation of the exocyst complex. J Immunotherapy Cancer. 2022;10:e004820.

  17. Li HJ, Fu XH, Zhao JJ, Li C, Li LM, Xia PY, et al. EXOC4 promotes diffuse-type gastric cancer metastasis via activating FAK signal. Mol Cancer Res. 2022;20:1021–34.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Kau TR, Way JC, Silver PA. Nuclear transport and cancer: from mechanism to intervention. Nat Rev Cancer. 2004;4:106–17.

    Article  PubMed  CAS  Google Scholar 

  19. Lorton BM, Shechter D. Cellular consequences of arginine methylation. Cell Mol Life Sci. 2019;76:2933–56.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Narita T, Weinert BT, Choudhary C. Functions and mechanisms of non-histone protein acetylation. Nat Rev Mol Cell Biol. 2019;20:156–74.

    Article  PubMed  CAS  Google Scholar 

  21. Delvecchio M, Gaucher J, Aguilar-Gurrieri C, Ortega E, Panne D. Structure of the p300 catalytic core and implications for chromatin targeting and HAT regulation. Nat Struct Mol Biol. 2013;20:1040.

    Article  PubMed  CAS  Google Scholar 

  22. Frit P, Amin H, Zahid S, Barboule N, Hall C, Matharu G, et al. Structural and functional insights into the interaction between Ku70/80 and Pol X family polymerases in NHEJ. Nat Commun. 2025;16:4208.

  23. Rinaldi C, Pizzul P, Casari E, Mangiagalli M, Tisi R, Longhese MP. The Ku complex promotes DNA end-bridging and this function is antagonized by Tel1/ATM kinase. Nucleic Acids Res. 2023;51:1783–802.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Zhu YX, Xia T, Chen DQ, Xiong X, Shi LH, Zuo YQ, et al. Promising role of protein arginine methyltransferases in overcoming anti-cancer drug resistance. Drug Resistance Updates. 2024;72:101016.

  25. Mihailidou C, Karamouzis MV, Schizas D, Papavassiliou AG. Co-targeting c-Met and DNA double-strand breaks (DSBs): therapeutic strategies in BRCA-mutated gastric carcinomas. Biochimie. 2017;142:135–43.

    Article  PubMed  CAS  Google Scholar 

  26. Olaizola I, Odriozola-Gimeno M, Olaizola P, Caballero-Camino FJ, Pastor-Toyos N, Tena-Garitaonaindia M, et al. New platinum derivatives selectively cause double-strand DNA breaks and death in naive and cisplatin-resistant cholangiocarcinomas. J Hepatol. 2025;83:1077–91.

  27. Japanese Gastric Canc A. Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer. 2011;14:101–12.

    Article  Google Scholar 

  28. Okines A, Verheij M, Allum W, Cunningham D, Cervantes A. Grp EGW. Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21:v50–v4.

    Article  PubMed  Google Scholar 

  29. Causse SZ, Marcion G, Chanteloup G, Uyanik B, Boudesco C, Grigorash BB, et al. HSP110 translocates to the nucleus upon genotoxic chemotherapy and promotes DNA repair in colorectal cancer cells. Oncogene. 2019;38:2767–77.

    Article  PubMed  CAS  Google Scholar 

  30. Tu WJ, Melino M, Dunn J, McCuaig RD, Bielefeldt-Ohmann H, Tsimbalyuk S, et al. In vivo inhibition of nuclear ACE2 translocation protects against SARS-CoV-2 replication and lung damage through epigenetic imprinting. Nat Commun. 2023;14:3680.

  31. Wu Q, Li G, Wen C, Zeng T, Fan Y, Liu C, et al. Monoubiquitination of p120-catenin is essential for TGFβ-induced epithelial-mesenchymal transition and tumor metastasis. Sci Adv. 2020;6:eaay9819.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Hu Z, Sui Q, Jin X, Shan G, Huang Y, Yi Y, et al. IL6-STAT3-C/EBPβ-IL6 positive feedback loop in tumor-associated macrophages promotes the EMT and metastasis of lung adenocarcinoma. J Exp Clin Cancer Res. 2024;43:63.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Tan Z, Sun W, Li Y, Jiao X, Zhu M, Zhang J, et al. Current progress of EMT: a new direction of targeted therapy for colorectal cancer with invasion and metastasis. Biomolecules. 2022;12:1723.

  34. Mengistu BA, Tsegaw T, Demessie Y, Getnet K, Bitew AB, Kinde MZ, et al. Comprehensive review of drug resistance in mammalian cancer stem cells: implications for cancer therapy. Cancer Cell Int. 2024;24:406.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Chen Y, Xiao MM, Mo YQ, Ma JL, Han YM, Li Q, et al. Nuclear porcupine mediates XRCC6/Ku70 S-palmitoylation in the DNA damage response. Exper Hematol Oncol. 2024;13:109.

  36. Wang Y, Czap MS, Kim H, Masaka PM, Wang HX, Beg MA, et al. The mammalian Ku70 C-terminus SAP domain is required to repair DNA damage. Nucleic Acids Res. 2025;53:gkaf499.

  37. Sui Y, Shen ZY, Pan RT, Ma R, Si RJ, Feng JF, et al. AHSA1-HSP90AA1 complex stabilized IFI6 and TGFB1 promotes mitochondrial stability and EMT in EGFR-mutated lung adenocarcinoma under Osimertinib pressure. Cell Death Dis. 2025;16:298.

  38. Cao XY, Li CQ, Xiao SY, Tang YL, Huang J, Zhao S, et al. Acetylation promotes TyrRS nuclear translocation to prevent oxidative damage. Proc Natl Acad Sci USA. 2017;114:687–92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Yildirim EC, Acikgoz Y, Ergun Y, Algin E, Bal O. Treatment outcomes and prognostic factors in N3 stage gastric cancer after curative resection: a real world data. Cancer Manag Res. 2023;15:1085–96.

    Article  Google Scholar 

  40. Yoon HI, Chang JS, Lim JS, Noh SH, Hyung WJ, An JY, et al. Defining the target volume for post-operative radiotherapy after D2 dissection in gastric cancer by CT-based vessel-guided delineation. Radiother Oncol. 2013;108:72–7.

    Article  PubMed  Google Scholar 

  41. Leong T, Smithers BM, Michael M, Haustermans K, Wong R, Gebski V, et al. Preoperative chemoradiotherapy for resectable gastric cancer. N Engl J Med. 2024;391:1810–21.

    Article  PubMed  CAS  Google Scholar 

  42. Zhou ML, Yang W, Wang YQ, Mo M, Hu R, Wang Y, et al. Adjuvant chemoradiotherapy versus adjuvant chemotherapy for patients with N3 gastric cancer after D2/R0 resection: a retrospective study based on propensity score analyses. Cancer Manag Res. 2019;11:4855–70.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Funding

This work was supported by Fujian Provincial Natural Science Foundation of China [Grant Number: 2024J011445]; and the Scientific Research Foundation of Zhongshan Hospital [Grant Number: ZY2024-003].

Author information

Author notes

  1. These authors contributed equally: Haojie Li, Haoyu Sun, Xu Yang, Wenchao Jiang, Xinyou Liu.

Authors and Affiliations

  1. Department of Gastrointestinal Surgery, Cancer Center, Gastric Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China

    Haojie Li, Haoyu Sun, Xu Yang, Wenchao Jiang, Chenyu Tian, Junjie Zhao, Yuanyuan Ruan, Jie Sun & Xuefei Wang

  2. Department of General Surgery, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China

    Haojie Li, Xinyou Liu, Bosen Li & Xuefei Wang

  3. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China

    Yuanyuan Ruan

  4. Clinical Research Center for Precision Medicine of Abdominal Tumor of Fujian Province, Xiamen, China

    Xuefei Wang

Authors
  1. Haojie Li
    View author publications

    Search author on:PubMed Google Scholar

  2. Haoyu Sun
    View author publications

    Search author on:PubMed Google Scholar

  3. Xu Yang
    View author publications

    Search author on:PubMed Google Scholar

  4. Wenchao Jiang
    View author publications

    Search author on:PubMed Google Scholar

  5. Xinyou Liu
    View author publications

    Search author on:PubMed Google Scholar

  6. Bosen Li
    View author publications

    Search author on:PubMed Google Scholar

  7. Chenyu Tian
    View author publications

    Search author on:PubMed Google Scholar

  8. Junjie Zhao
    View author publications

    Search author on:PubMed Google Scholar

  9. Yuanyuan Ruan
    View author publications

    Search author on:PubMed Google Scholar

  10. Jie Sun
    View author publications

    Search author on:PubMed Google Scholar

  11. Xuefei Wang
    View author publications

    Search author on:PubMed Google Scholar

Contributions

Conception and design: HJL, HYS, JS, XFW and YYR; Data acquisition, analysis, and interpretation: JS and JJZ; Investigation: HYS, JS, XY and WCJ; Acquisition of patient specimens: XYL, BSL, CYT; Paper drafting and revising: HJL, HYS, and WCJ; and paper writing: HYS. All authors approved the final version of the paper.

Corresponding authors

Correspondence to Junjie Zhao, Yuanyuan Ruan, Jie Sun or Xuefei Wang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval

The collection and processing of patients’ specimens as well as animal experiments for the study have been reviewed and approved by the Ethical Committee of Zhongshan Hospital of Fudan University.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, H., Sun, H., Yang, X. et al. Acetylation-dependent nuclear translocation of EXOC4 regulates KU70 methylation to facilitate non-homologous end joining. Cell Death Differ (2026). https://doi.org/10.1038/s41418-026-01705-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • DOI: https://doi.org/10.1038/s41418-026-01705-w

Search

Advanced search

Quick links