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USP10-mediated Ku70/80 stabilization inhibits PANoptosis and promotes chemoresistance in colorectal cancer

Oncogene (2025)Cite this article

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Abstracts

Chemotherapy is a widely used treatment for advanced colorectal cancer; however, its efficacy is often limited by chemotherapy resistance, the complex mechanisms of which remain poorly understood. Interestingly, we discovered that the expression levels of USP10 increase in tumor cells in response to chemotherapy, contributing to chemotherapy resistance. Under chemotherapy-induced stress, USP10 stabilizes the Ku70/80 complex in colorectal cancer cells, promoting DNA repair, reducing intracellular ROS levels, and mitigating PANoptosis, which leads to chemotherapy resistance. Additionally, the promoter activity of USP10 is regulated by the non-coding RNA Linc01106. This study also confirmed that the absence of USP10 enhances chemotherapy sensitivity in colorectal cancer cells, providing a potential strategy for overcoming chemotherapy resistance and improving therapeutic outcomes.

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Fig. 1: USP10 positively correlates with malignancy and Ku70/80 abundance in CRC.
Fig. 2: USP10 can inhibit the level of DNA damage in Oxa treatment.
Fig. 3: USP10 interacts with the Ku70/80 complex and stabilizes the protein abundance.
Fig. 4: USP10 resists Oxa-induced DNA damage through stabilizing Ku70/80 complex protein abundance.
Fig. 5: Silencing of USP10 improves the chemosensitivity of Oxa by inducing cellular PANoptosis.
Fig. 6: Linc01106 induces chemoresistance by promoting USP10 expression.
Fig. 7: Oxidative stress levels play an important role in USP10-mediated chemotherapy sensitivity.
Fig. 8: Xenograft tumor model validates USP10 promoting chemoresistance through DNA repair.
Fig. 9: Schematic diagram of USP10 inducing chemoresistance through modulation of the Ku70/80 complex.

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Data availability

The data used and/or analyzed in this study can be obtained from the corresponding author on reasonable request.

References

  1. Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB. Colorectal cancer. Lancet. 2019;394:1467–80.

    Article  PubMed  Google Scholar 

  2. Chen W, Zhu Y, Zhang Z, Sun X. Advances in Salmonella Typhimurium-based drug delivery system for cancer therapy. Advanced Drug Deliv Rev. 2022;185:114295.

    Article  CAS  Google Scholar 

  3. Guo Q, Wang H, Duan J, Luo W, Zhao R, Shen Y, et al. An alternatively spliced p62 isoform confers resistance to chemotherapy in breast cancer. Cancer Res. 2022;82:4001–15.

    Article  CAS  PubMed  Google Scholar 

  4. Pothuraju R, Rachagani S, Krishn SR, Chaudhary S, Nimmakayala RK, Siddiqui JA, et al. Molecular implications of MUC5AC-CD44 axis in colorectal cancer progression and chemoresistance. Mol Cancer. 2020;19:37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Yu T, Guo F, Yu Y, Sun T, Ma D, Han J, et al. Fusobacterium nucleatum promotes chemoresistance to colorectal cancer by modulating autophagy. Cell. 2017;170:548–63.e516.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Jin W. Role of JAK/STAT3 signaling in the regulation of metastasis, the transition of cancer stem cells, and chemoresistance of cancer by epithelial-mesenchymal transition. Cells. 2020;9:217.

  7. Huang R, Zhou PK. DNA damage repair: historical perspectives, mechanistic pathways and clinical translation for targeted cancer therapy. Signal Transduct Target Ther. 2021;6:254.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Srinivas US, Tan BWQ, Vellayappan BA, Jeyasekharan AD. ROS and the DNA damage response in cancer. Redox Biol. 2019;25:101084.

    Article  CAS  PubMed  Google Scholar 

  9. Dasari S, Tchounwou PB. Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol. 2014;740:364–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kang L, Tian Y, Xu S, Chen H. Oxaliplatin-induced peripheral neuropathy: clinical features, mechanisms, prevention and treatment. J Neurol. 2021;268:3269–82.

    Article  CAS  PubMed  Google Scholar 

  11. Li H, Wang C, Lan L, Yan L, Li W, Evans I, et al. METTL3 promotes oxaliplatin resistance of gastric cancer CD133+stem cells by promoting PARP1 mRNA stability. Cell Mol Life Sci. 2022;79:135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hanker AB, Sudhan DR, Arteaga CL. Overcoming endocrine resistance in breast cancer. Cancer Cell. 2020;37:496–513.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Özeş AR, Miller DF, Özeş ON, Fang F, Liu Y, Matei D, et al. NF-κB-HOTAIR axis links DNA damage response, chemoresistance and cellular senescence in ovarian cancer. Oncogene. 2016;35:5350–61.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Hung T, Wang Y, Lin MF, Koegel AK, Kotake Y, Grant GD, et al. Extensive and coordinated transcription of noncoding RNAs within cell-cycle promoters. Nat Genet. 2011;43:621–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lin JF, Hu PS, Wang YY, Tan YT, Yu K, Liao K, et al. Phosphorylated NFS1 weakens oxaliplatin-based chemosensitivity of colorectal cancer by preventing PANoptosis. Signal Transduct Target Ther. 2022;7:54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. He C, Kawaguchi K, Toi M. DNA damage repair functions and targeted treatment in breast cancer. Breast Cancer. 2020;27:355–62.

    Article  PubMed  Google Scholar 

  17. Demin AA, Hirota K, Tsuda M, Adamowicz M, Hailstone R, Brazina J, et al. XRCC1 prevents toxic PARP1 trapping during DNA base excision repair. Mol Cell. 2021;81:3018–30.e3015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Morio T, Kim H. Ku, Artemis, and ataxia-telangiectasia-mutated: signalling networks in DNA damage. Int J Biochem Cell Biol. 2008;40:598–603.

    Article  CAS  PubMed  Google Scholar 

  19. Yu Y, Liu T, Yu G, Wang H, Du Z, Chen Y, et al. PRDM15 interacts with DNA-PK-Ku complex to promote radioresistance in rectal cancer by facilitating DNA damage repair. Cell Death Dis. 2022;13:978.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lee SH, Kim CH. DNA-dependent protein kinase complex: a multifunctional protein in DNA repair and damage checkpoint. Mol Cells. 2002;13:159–66.

    Article  CAS  PubMed  Google Scholar 

  21. Yoshida K, Fujita M. DNA damage responses that enhance resilience to replication stress. Cellular Mol Life Sci. 2021;78:6763–73.

    Article  CAS  Google Scholar 

  22. Dewson G, Eichhorn PJA, Komander D. Deubiquitinases in cancer. Nat Rev Cancer. 2023;23:842–62.

    Article  CAS  PubMed  Google Scholar 

  23. Komander D, Clague MJ, Urbé S. Breaking the chains: structure and function of the deubiquitinases. Nat Rev Mol Cell Biol. 2009;10:550–63.

    Article  CAS  PubMed  Google Scholar 

  24. Komander D, Rape M. The ubiquitin code. Annu Rev Biochem. 2012;81:203–29.

    Article  CAS  PubMed  Google Scholar 

  25. Zella D, Curreli S, Benedetti F, Krishnan S, Cocchi F, Latinovic OS, et al. Mycoplasma promotes malignant transformation in vivo, and its DnaK, a bacterial chaperone protein, has broad oncogenic properties. Proc Natl Acad Sci USA. 2018;115:E12005–e12014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zhao X, Ma Y, Li J, Sun X, Sun Y, Qu F, et al. The AEG-1-USP10-PARP1 axis confers radioresistance in esophageal squamous cell carcinoma via facilitating homologous recombination-dependent DNA damage repair. Cancer Lett. 2023;577:216440.

    Article  CAS  PubMed  Google Scholar 

  27. Reissland M, Hartmann O, Tauch S, Bugter JM, Prieto-Garcia C, Schulte C, et al. USP10 drives cancer stemness and enables super-competitor signalling in colorectal cancer. Oncogene. 2024;43:3645–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Dou N, Hu Q, Li L, Wu Q, Li Y, Gao Y. USP32 promotes tumorigenesis and chemoresistance in gastric carcinoma via upregulation of SMAD2. Int J Biol Sci. 2020;16:1648–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lin P, Lin C, He R, Chen H, Teng Z, Yao H, et al. TRAF6 regulates the abundance of RIPK1 and inhibits the RIPK1/RIPK3/MLKL necroptosis signaling pathway and affects the progression of colorectal cancer. Cell Death Dis. 2023;14:6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 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  CAS  PubMed  Google Scholar 

  31. Kuo LJ, Yang LX. Gamma-H2AX - a novel biomarker for DNA double-strand breaks. In Vivo. 2008;22:305–9.

  32. Kabakov AE, Gabai VL. Cell death and survival assays. Methods Mol Biol. 2018;1709:107–27.

    Article  CAS  PubMed  Google Scholar 

  33. Kayagaki N, Kornfeld OS, Lee BL, Stowe IB, O’Rourke K, Li Q, et al. NINJ1 mediates plasma membrane rupture during lytic cell death. Nature. 2021;591:131–6.

    Article  CAS  PubMed  Google Scholar 

  34. Yuan J, Luo K, Zhang L, Cheville JC, Lou Z. USP10 regulates p53 localization and stability by deubiquitinating p53. Cell. 2010;140:384–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wang X, Xia S, Li H, Wang X, Li C, Chao Y, et al. The deubiquitinase USP10 regulates KLF4 stability and suppresses lung tumorigenesis. Cell Death Differ. 2020;27:1747–64.

    Article  CAS  PubMed  Google Scholar 

  36. Wu F, Du Y, Yang J, Shao B, Mi Z, Yao Y, et al. Peroxidase-like active nanomedicine with dual glutathione depletion property to restore oxaliplatin chemosensitivity and promote programmed cell death. ACS Nano. 2022;16:3647–63.

    Article  CAS  PubMed  Google Scholar 

  37. Zhang Q, Deng T, Zhang H, Zuo D, Zhu Q, Bai M, et al. Adipocyte-derived exosomal MTTP suppresses ferroptosis and promotes chemoresistance in colorectal cancer. Adv Sci. 2022;9:e2203357.

    Article  Google Scholar 

  38. Takahashi M, Higuchi M, Makokha GN, Matsuki H, Yoshita M, Tanaka Y, et al. HTLV-1 Tax oncoprotein stimulates ROS production and apoptosis in T cells by interacting with USP10. Blood. 2013;122:715–25.

    Article  CAS  PubMed  Google Scholar 

  39. Aulas A, Finetti P, Lyons SM, Bertucci F, Birnbaum D, Acquaviva C, et al. Revisiting the concept of stress in the prognosis of solid tumors: a role for stress granules proteins? Cancers. 2020;12:2470.

  40. Zhu H, Yan F, Yuan T, Qian M, Zhou T, Dai X, et al. USP10 promotes proliferation of hepatocellular carcinoma by deubiquitinating and stabilizing YAP/TAZ. Cancer Res. 2020;80:2204–16.

    Article  CAS  PubMed  Google Scholar 

  41. Hu C, Zhang M, Moses N, Hu CL, Polin L, Chen W, et al. The USP10-HDAC6 axis confers cisplatin resistance in non-small cell lung cancer lacking wild-type p53. Cell Death Dis. 2020;11:328.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kubaichuk K, Kietzmann T. USP10 contributes to colon carcinogenesis via mTOR/S6K mediated HIF-1α but not HIF-2α protein synthesis. Cells. 2023;12:1585.

  43. Fisusi FA, Akala EO. Drug combinations in breast cancer therapy. Pharm Nanotechnol. 2019;7:3–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Wei G, Wang Y, Yang G, Wang Y, Ju R. Recent progress in nanomedicine for enhanced cancer chemotherapy. Theranostics. 2021;11:6370–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. de Armas S, Huertas-Ayala C, Chan RY, Chi YY, Huh WW, Termuhlen A, et al. Survival of pediatric Hodgkin lymphoma patients treated with doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) at a single institution. Pediatr Blood Cancer. 2022;69:e29601.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Kumari N, Antil H, Kumari S, Raghavan SC. Deficiency of ligase IV leads to reduced NHEJ, accumulation of DNA damage, and can sensitize cells to cancer therapeutics. Genomics. 2023;115:110731.

    Article  CAS  PubMed  Google Scholar 

  47. Mailloux A, Grenet K, Bruneel A, Bénéteau-Burnat B, Vaubourdolle M, Baudin B. Anticancer drugs induce necrosis of human endothelial cells involving both oncosis and apoptosis. Eur J Cell Biol. 2001;80:442–9.

    Article  CAS  PubMed  Google Scholar 

  48. Nishi R, Wijnhoven PWG, Kimura Y, Matsui M, Konietzny R, Wu Q, et al. The deubiquitylating enzyme UCHL3 regulates Ku80 retention at sites of DNA damage. Sci Rep. 2018;8:17891.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Sharma A, Alswillah T, Kapoor I, Debjani P, Willard B, Summers MK, et al. USP14 is a deubiquitinase for Ku70 and critical determinant of non-homologous end joining repair in autophagy and PTEN-deficient cells. Nucleic Acids Res. 2020;48:736–47.

    CAS  PubMed  Google Scholar 

  50. Chen H, Li Y, Li H, Chen X, Fu H, Mao D, et al. NBS1 lactylation is required for efficient DNA repair and chemotherapy resistance. Nature. 2024;631:663–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Wei Z, Zeng K, Hu J, Li X, Huang F, Zhang B, et al. USP10 deubiquitinates Tau, mediating its aggregation. Cell Death Dis. 2022;13:726.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Pan L, Chen Z, Wang L, Chen C, Li D, Wan H, et al. Deubiquitination and stabilization of T-bet by USP10. Biochem Biophys Res Commun. 2014;449:289–94.

    Article  CAS  PubMed  Google Scholar 

  53. Xia X, Hu T, He J, Xu Q, Yu C, Liu X, et al. USP10 deletion inhibits macrophage-derived foam cell formation and cellular-oxidized low density lipoprotein uptake by promoting the degradation of CD36. Aging. 2020;12:22892–905.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Sola-Sevilla N, Puerta E. SIRT2 as a potential new therapeutic target for Alzheimer’s disease. Neural Regen Res. 2024;19:124–31.

    Article  CAS  PubMed  Google Scholar 

  55. Hayes JD, Dinkova-Kostova AT, Tew KD. Oxidative stress in cancer. Cancer Cell. 2020;38:167–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Sies H, Jones DP. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat Rev Mol Cell Biol. 2020;21:363–83.

    Article  CAS  PubMed  Google Scholar 

  57. Chen H, Yoshioka H, Kim GS, Jung JE, Okami N, Sakata H, et al. Oxidative stress in ischemic brain damage: mechanisms of cell death and potential molecular targets for neuroprotection. Antioxid Redox Signal. 2011;14:1505–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Chi H, Peng G, Wang R, Yang F, Xie X, Zhang J, et al. Cuprotosis programmed-cell-death-related lncRNA signature predicts prognosis and immune landscape in PAAD patients. Cells. 2022;11:3436.

  59. Wu Z, Lu Z, Li L, Ma M, Long F, Wu R, et al. Identification and validation of ferroptosis-related LncRNA signatures as a novel prognostic model for colon cancer. Front Immunol. 2021;12:783362.

    Article  CAS  PubMed  Google Scholar 

  60. Zhang Y, Luo M, Cui X, O’Connell D, Yang Y. Long noncoding RNA NEAT1 promotes ferroptosis by modulating the miR-362-3p/MIOX axis as a ceRNA. Cell Death Differ. 2022;29:1850–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Gao X, Yu L, Zhang J, Xue P. Silencing of long non-coding RNA LINC01106 suppresses the proliferation, migration and invasion of endometrial cancer cells through regulating the miR-449a/MET axis. Onco Targets Ther. 2020;13:9643–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Guo K, Gong W, Wang Q, Gu G, Zheng T, Li Y, et al. LINC01106 drives colorectal cancer growth and stemness through a positive feedback loop to regulate the Gli family factors. Cell Death Dis. 2020;11:869.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Hong S, Li Q, Yang Y, Jing D, Zhu F. Silencing of long non-coding RNA LINC01106 represses malignant behaviors of gastric cancer cells by targeting miR-34a-5p/MYCN axis. Mol Biotechnol. 2022;64:144–55.

    Article  CAS  PubMed  Google Scholar 

  64. Liu J, Tian C, Qiao J, Deng K, Ye X, Xiong L. m6A methylation-mediated stabilization of LINC01106 suppresses bladder cancer progression by regulating the miR-3148/DAB1 axis. Biomedicines. 2024;12:114.

  65. Meng L, Xing Z, Guo Z, Liu Z. LINC01106 post-transcriptionally regulates ELK3 and HOXD8 to promote bladder cancer progression. Cell Death Dis. 2020;11:1063.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This study was supported by the National Natural Science Foundation of China (No. 82273361), the Joint Funds for the Innovation of Science and Technology, Fujian Province (No. 2024Y9208), the National Natural Science Foundation of Fujian Province (No. 2023J06032).

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  1. These authors contributed equally: Penghang Lin, Chunlin Lin.

Authors and Affiliations

  1. Department of Gastrointestinal Surgery 2 Section, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China

    Penghang Lin, Chunlin Lin, Zuhong Teng, Songyi Liu, Xiang Lin, Ruofan He, Hengxin Yao, Jianxin Ye & Guangwei Zhu

  2. Department of Gastrointestinal Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China

    Penghang Lin, Chunlin Lin, Zuhong Teng, Songyi Liu, Xiang Lin, Ruofan He, Hengxin Yao, Jianxin Ye & Guangwei Zhu

  3. Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China

    Zuhong Teng, Songyi Liu, Xiang Lin, Ruofan He & Hengxin Yao

  4. Fujian Key Laboratory of Precision Medicine for Cancer, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China

    Zuhong Teng, Songyi Liu, Xiang Lin, Ruofan He & Hengxin Yao

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Contributions

JXY and GWZ designed this experiment. PHL and CLL conducted experiments. ZHT and SYL analyzed data. XL, RFH, and HXY explained the experimental results. PHL and CLL prepared these figures. GWZ and PHL wrote this manuscript. JXY and ZHT contributed to manuscript editing. All authors participated in reading and discussing the manuscript.

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Correspondence to Jianxin Ye or Guangwei Zhu.

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The authors declare no competing interests.

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This study was approved by the Institutional Review Board (IRB) of the First Affiliated Hospital of Fujian Medical University (permit number: MRCTA, ECFAH of FMU [2022] 515) and conducted in strict accordance with the Declaration of Helsinki. Written informed consent was obtained from each patient before enrollment. All animal experiments were reviewed by the Animal Management and Use Ethics Committee of Fujian Medical University and relevant animal associations (permit number: IACUC FJMU 2023-Y-0975). Every effort was made to minimize animal suffering.

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Lin, P., Lin, C., Teng, Z. et al. USP10-mediated Ku70/80 stabilization inhibits PANoptosis and promotes chemoresistance in colorectal cancer. Oncogene (2025). https://doi.org/10.1038/s41388-025-03570-2

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