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circSETD3 confers radiotherapy resistance in nasopharyngeal carcinoma by attenuating ER stress-induced autophagy and apoptosis via PDIA6 upregulation

Oncogene volume 45, pages 368–382 (2026)Cite this article

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Abstract

Nasopharyngeal carcinoma (NPC) is a malignant tumor of the head and neck with a high prevalence in Southeast Asia. Although radiotherapy remains the primary treatment modality, resistance to radiation in a subset of patients with advanced-stage disease significantly limits therapeutic outcomes, and the underlying molecular mechanisms remain poorly understood. In this study, we identified the circular RNA circSETD3 as a critical regulator of radioresistance in NPC. Functional assays in both in vitro and in vivo models demonstrated that circSETD3 enhances radioresistance by suppressing autophagy and apoptosis. Mechanistically, circSETD3 binds to the 3′ untranslated region (3′UTR) of PDIA6 mRNA, stabilizing the transcript and increasing PDIA6 protein expression and its localization to the endoplasmic reticulum (ER). Elevated PDIA6 promotes the refolding of radiation-induced misfolded proteins, maintains ER proteostasis, and suppresses the unfolded protein response (UPR). This alleviation of ER stress reduces radiation-induced autophagy and apoptosis, ultimately enhancing NPC cell survival under radiotherapeutic stress. Together, these findings reveal a pivotal role for circSETD3 in promoting NPC radioresistance via PDIA6-mediated modulation of endoplasmic reticulum stress, and they provide a novel mechanistic framework and promising therapeutic target for improving radiotherapy efficacy in NPC.

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Fig. 1: circSETD3 promotes radioresistance in NPC cells.
Fig. 2: circSETD3 inhibits autophagy and apoptosis to promote radioresistance in NPC cells.
Fig. 3: PDIA6 suppresses autophagy and apoptosis, contributing to radioresistance in NPC cells.
Fig. 4: circSETD3 enhances radioresistance by upregulating PDIA6 to suppress radiation-induced autophagy and apoptosis in NPC cells.
Fig. 5: circSETD3 binds to the 3′UTR of PDIA6 mRNA and enhances its stability and expression.
Fig. 6: circSETD3 sustains protein homeostasis and suppresses ER stress.
Fig. 7: Expression of circSETD3, PDIA6, and autophagy- and apoptosis-related markers in xenograft tumor tissues.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Tang LL, Chen YP, Chen CB, Chen MY, Chen NY, Chen XZ, et al. The Chinese Society of Clinical Oncology (CSCO) clinical guidelines for the diagnosis and treatment of nasopharyngeal carcinoma. Cancer Commun. 2021;41:1195–227.

    Article  Google Scholar 

  2. Chen LL. The expanding regulatory mechanisms and cellular functions of circular RNAs. Nat Rev Mol Cell Biol. 2020;21:475–90.

    Article  PubMed  CAS  Google Scholar 

  3. Qu H, Wang Y, Yan Q, Fan C, Zhang X, Wang D, et al. CircCDYL2 bolsters radiotherapy resistance in nasopharyngeal carcinoma by promoting RAD51 translation initiation for enhanced homologous recombination repair. J Exp Clin Cancer Res. 2024;43:122.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Wang D, Tang L, Chen M, Gong Z, Fan C, Qu H, et al. Nanocarriers targeting circular RNA ADARB1 boost radiosensitivity of nasopharyngeal carcinoma through synergically promoting ferroptosis. ACS Nano. 2024;18:31055–75.

    Article  PubMed  CAS  Google Scholar 

  5. Ge J, Meng Y, Guo J, Chen P, Wang J, Shi L, et al. Human papillomavirus-encoded circular RNA circE7 promotes immune evasion in head and neck squamous cell carcinoma. Nat Commun. 2024;15:8609.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Wang D, Zuo S, Ge J, Qu H, Wu J, Yi N, et al. circTP63-N suppresses the proliferation and metastasis of nasopharyngeal carcinoma via engaging with HSP90AB1 to modulate the YAP1/Hippo signaling pathway. Sci China Life Sci. 2025;68:689–705.

    Article  PubMed  CAS  Google Scholar 

  7. Peng M, Zhang S, Wu P, Hou X, Wang D, Ge J, et al. Circular RNA circCLASP2 promotes nasopharyngeal carcinoma progression through binding to DHX9 to enhance PCMT1 translation. Mol cancer. 2025;24:67.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Fan C, Tan F, Wu J, Zeng Z, Guo W, Huang H, et al. CircCCNB1 inhibits vasculogenic mimicry by sequestering NF90 to promote miR-15b-5p and miR-7-1-3p processing in nasopharyngeal carcinoma. Mol Oncol. 2025;19:1876–93.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Yang Y, Wang Y, Qu H, Wang D, Ge J, Wu P, et al. CircCDYL promotes glycolysis to drive the progression of nasopharyngeal carcinoma. J Adv Res. 2025;26:S2090–1232.

    Google Scholar 

  10. Wang D, Mendoza JJ, Xiang P, Zhang Y, Tang L, Zhang J, et al. circADARB1 enhances ZEB1 expression in an m(6)A-dependent manner to promote the invasion and migration of nasopharyngeal carcinoma. Int J Biol Macromol. 2025;318:145187.

    Article  PubMed  CAS  Google Scholar 

  11. Zeng H, Ge J, Meng Y, Wang Q, Yang M, Zeng Z, et al. Research progress on the role and mechanism of circular RNA in drug resistance of head and neck squamous cell carcinoma. Cancer Drug Resist. 2024;7:31.

    PubMed  PubMed Central  CAS  Google Scholar 

  12. Tang L, Xiong W, Zhang L, Wang D, Wang Y, Wu Y, et al. circSETD3 regulates MAPRE1 through miR-615-5p and miR-1538 sponges to promote migration and invasion in nasopharyngeal carcinoma. Oncogene. 2021;40:307–21.

    Article  PubMed  CAS  Google Scholar 

  13. Lv X, Lu X, Cao J, Luo Q, Ding Y, Peng F, et al. Modulation of the proteostasis network promotes tumor resistance to oncogenic KRAS inhibitors. Science. 2023;381:eabn4180.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Wu Y, Song Y, Wang R, Wang T. Molecular mechanisms of tumor resistance to radiotherapy. Mol Cancer. 2023;22:96.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Bai Y, Liu X, Qi X, Liu X, Peng F, Li H, et al. PDIA6 modulates apoptosis and autophagy of non-small cell lung cancer cells via the MAP4K1/JNK signaling pathway. EBioMedicine. 2019;42:311–25.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Lee S, Min Kim S, Dotimas J, Li L, Feener EP, Baldus S, et al. Thioredoxin-interacting protein regulates protein disulfide isomerases and endoplasmic reticulum stress. EMBO Mol Med. 2014;6:732–43.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Mestre-Farràs N, Guerrero S, Bley N, Rivero E, Coll O, Borràs E, et al. Melanoma RBPome identification reveals PDIA6 as an unconventional RNA-binding protein involved in metastasis. Nucleic Acids Res. 2022;50:8207–25.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Rosell R, Karachaliou N. Disulfide isomerase family-6 mediates cisplatin resistance by interfering with apoptosis and autophagy. EBioMedicine. 2019;42:20–21.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Tufo G, Jones AW, Wang Z, Hamelin J, Tajeddine N, Esposti DD, et al. The protein disulfide isomerases PDIA4 and PDIA6 mediate resistance to cisplatin-induced cell death in lung adenocarcinoma. Cell Death Differ. 2014;21:685–95.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Zhong Y, Du Y, Yang X, Mo Y, Fan C, Xiong F, et al. Circular RNAs function as ceRNAs to regulate and control human cancer progression. Mol Cancer. 2018;17:79.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Yang X, Yang Y, Sun BF, Chen YS, Xu JW, Lai WY, et al. 5-methylcytosine promotes mRNA export - NSUN2 as the methyltransferase and ALYREF as an m(5)C reader. Cell Res. 2017;27:606–25.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Warminski M, Mamot A, Depaix A, Kowalska J, Jemielity J. Chemical modifications of mRNA ends for therapeutic applications. Acc Chem Res. 2023;56:2814–26.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Chen X, Cubillos-Ruiz JR. Endoplasmic reticulum stress signals in the tumour and its microenvironment. Nat Rev Cancer. 2021;21:71–88.

    Article  PubMed  CAS  Google Scholar 

  24. Hetz C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol. 2012;13:89–102.

    Article  PubMed  CAS  Google Scholar 

  25. Marciniak SJ, Chambers JE, Ron D. Pharmacological targeting of endoplasmic reticulum stress in disease. Nat Rev Drug Discov. 2022;21:115–40.

    Article  PubMed  CAS  Google Scholar 

  26. Oakes SA, Papa FR. The role of endoplasmic reticulum stress in human pathology. Annu Rev Pathol. 2015;10:173–94.

    Article  PubMed  CAS  Google Scholar 

  27. Salaroglio IC, Panada E, Moiso E, Buondonno I, Provero P, Rubinstein M, et al. PERK induces resistance to cell death elicited by endoplasmic reticulum stress and chemotherapy. Mol cancer. 2017;16:91.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Ngo LH, Bert AG, Dredge BK, Williams T, Murphy V, Li W, et al. Nuclear export of circular RNA. Nature. 2024;627:212–20.

    Article  PubMed  CAS  Google Scholar 

  29. Liu D, Dredge BK, Bert AG, Pillman KA, Toubia J, Guo W, et al. ESRP1 controls biogenesis and function of a large abundant multiexon circRNA. Nucleic Acids Res. 2024;52:1387–403.

    Article  PubMed  CAS  Google Scholar 

  30. Liang Y, Cen J, Huang Y, Fang Y, Wang Y, Shu G, et al. CircNTNG1 inhibits renal cell carcinoma progression via HOXA5-mediated epigenetic silencing of Slug. Mol Cancer. 2022;21:224.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Xu L, Feng X, Hao X, Wang P, Zhang Y, Zheng X, et al. CircSETD3 (Hsa_circ_0000567) acts as a sponge for microRNA-421 inhibiting hepatocellular carcinoma growth. J Exp Clin Cancer Res. 2019;38:98.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Huang Y, Dai Y, Wen C, He S, Shi J, Zhao D, et al. circSETD3 contributes to acquired resistance to gefitinib in non-small-cell lung cancer by targeting the miR-520h/ABCG2 pathway. Mol Ther Nucleic Acids. 2020;21:885–99.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Tian Y, Gao P, Dai D, Chen L, Chu X, Mei X. Circular RNA circSETD3 hampers cell growth, migration, and stem cell properties in bladder cancer through sponging miR-641 to upregulate PTEN. Cell Cycle. 2021;20:1589–602.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Chen Q, Deng Q, Pan Y, Ding X, Liu J. Hypoxia-induced miR-653 enhances colorectal cancer progression by targeting circSETD3/KLF6 axis. J Cancer. 2023;14:163–73.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Fessart D, Robert J, Hartog C, Chevet E, Delom F, Babin G. The Anterior GRadient (AGR) family proteins in epithelial ovarian cancer. J Exp Clin Cancer Res. 2021;40:271.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Shergalis AG, Hu S, Bankhead A 3rd, Neamati N. Role of the ERO1-PDI interaction in oxidative protein folding and disease. Pharm Ther. 2020;210:107525.

    Article  CAS  Google Scholar 

  37. Duncan RM, Reyes L, Moats K, Robinson RM, Murphy SA, Kaur B, et al. ATF3 coordinates antitumor synergy between epigenetic drugs and protein disulfide isomerase inhibitors. Cancer Res. 2020;80:3279–91.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Liu Y, Ji W, Shergalis A, Xu J, Delaney AM, Calcaterra A, et al. Activation of the unfolded protein response via inhibition of protein disulfide isomerase decreases the capacity for DNA repair to sensitize glioblastoma to radiotherapy. Cancer Res. 2019;79:2923–32.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Ma Y, Liu E, Fan H, Li C, Huang P, Cui M, et al. RBM47 promotes cell proliferation and immune evasion by upregulating PDIA6: a novel mechanism of pancreatic cancer progression. J Transl Med. 2024;22:1164.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Wu P, Zhang H, Qi L, Tang Q, Tang Y, Xie Z, et al. Identification of ERp29 as a biomarker for predicting nasopharyngeal carcinoma response to radiotherapy. Oncol Rep. 2012;27:987–94.

    Article  PubMed  CAS  Google Scholar 

  41. Niu X, You Q, Hou K, Tian Y, Wei P, Zhu Y, et al. Autophagy in cancer development, immune evasion, and drug resistance. Drug Resist Updat. 2025;78:101170.

    Article  PubMed  CAS  Google Scholar 

  42. Wang Z, Ren X, Li Y, Qiu L, Wang D, Liu A, et al. Reactive oxygen species amplifier for apoptosis-ferroptosis mediated high-efficiency radiosensitization of tumors. ACS Nano. 2024;18:10288–301.

    Article  PubMed  CAS  Google Scholar 

  43. Mizushima N, Levine B. Autophagy in human diseases. N Engl J Med. 2020;383:1564–76.

    Article  PubMed  CAS  Google Scholar 

  44. Debnath J, Gammoh N, Ryan KM. Autophagy and autophagy-related pathways in cancer. Nat Rev Mol Cell Biol. 2023;24:560–75.

    Article  PubMed  CAS  Google Scholar 

  45. Wang L, Klionsky DJ, Shen HM. The emerging mechanisms and functions of microautophagy. Nat Rev Mol Cell Biol. 2023;24:186–203.

    Article  PubMed  CAS  Google Scholar 

  46. Mace PD, Day CL. A massive machine regulates cell death. Science. 2023;379:1093–4.

    Article  PubMed  CAS  Google Scholar 

  47. Yuan J, Ofengeim D. A guide to cell death pathways. Nat Rev Mol Cell Biol. 2024;25:379–95.

    Article  PubMed  CAS  Google Scholar 

  48. Czabotar PE, Garcia-Saez AJ. Mechanisms of BCL-2 family proteins in mitochondrial apoptosis. Nat Rev Mol Cell Biol. 2023;24:732–48.

    Article  PubMed  CAS  Google Scholar 

  49. Liu K, Chen H, Li Y, Wang B, Li Q, Zhang L, et al. Autophagy flux in bladder cancer: cell death crosstalk, drug and nanotherapeutics. Cancer Lett. 2024;591:216867.

    Article  PubMed  CAS  Google Scholar 

  50. Urra H, Dufey E, Avril T, Chevet E, Hetz C. Endoplasmic reticulum stress and the hallmarks of cancer. Trends Cancer. 2016;2:252–62.

    Article  PubMed  Google Scholar 

  51. Meng B, Xu M, Chen Z, You J, Zhou R, Guan J, et al. SIRT7 sustains tumor development and radioresistance by repressing endoplasmic reticulum stress-induced apoptosis in cutaneous melanoma. Cell Signal. 2024;116:111058.

    Article  PubMed  CAS  Google Scholar 

  52. Song L, Liu H, Ma L, Zhang X, Jiang Z, Jiang C. Inhibition of autophagy by 3-MA enhances endoplasmic reticulum stress-induced apoptosis in human nasopharyngeal carcinoma cells. Oncol Lett. 2013;6:1031–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Zheng X, Jin X, Liu X, Liu B, Li P, Ye F, et al. Inhibition of endoplasmic reticulum stress-induced autophagy promotes the killing effect of X-rays on sarcoma in mice. Biochem Biophys Res Commun. 2020;522:612–7.

    Article  PubMed  CAS  Google Scholar 

  54. Feng X, Lv W, Wang S, He Q. miR‑495 enhances the efficacy of radiotherapy by targeting GRP78 to regulate EMT in nasopharyngeal carcinoma cells. Oncol Rep. 2018;40:1223–32.

    PubMed  PubMed Central  CAS  Google Scholar 

  55. Eletto D, Eletto D, Dersh D, Gidalevitz T, Argon Y. Protein disulfide isomerase A6 controls the decay of IRE1α signaling via disulfide-dependent association. Mol Cell. 2014;53:562–76.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

The authors acknowledge BioRender (www.biorender.com) for the creation of Fig. 7C.

Funding

This work was supported by the National Natural Science Foundation of China (82503155, 82472711, 82302979 and U21A20382), the Natural Science Foundation of Hunan Province (2025JJ60500, 2025JJ20099, 2025JJ50590 and 2024JJ3036), the Key Research Development Program of Hunan Province (2024PT5102 and 2024DK2007) and the Central South University Graduate Research and Innovation Project (2024ZZTS0859).

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Authors and Affiliations

  1. NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China

    Pingjuan Xiang, Yi Zhang, Juana Jessica Mendoza, Bo Xiang, Zhaoyang Zeng, Pan Chen, Dan Wang & Wei Xiong

  2. Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and Xiangya School of Basic Medicine Sciences, Central South University, Changsha, Hunan, China

    Pingjuan Xiang, Le Tang, Yi Zhang, Juana Jessica Mendoza, Qijia Yan, Lei Shi, Bo Xiang, Zhaoyang Zeng, Pan Chen, Dan Wang & Wei Xiong

  3. Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China

    Qijia Yan

  4. Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China

    Lei Shi

  5. Furong Laboratory, Changsha, Hunan, China

    Bo Xiang, Zhaoyang Zeng, Pan Chen, Dan Wang & Wei Xiong

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  1. Pingjuan Xiang
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  2. Le Tang
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Contributions

WX and DW conceived and designed the project. PX completed most experiments and wrote the manuscript. LT, YZ, and JJM performed some of the experiments. QY and LS collected tissue samples. BX and ZZ revised the manuscript. PC performed the data analysis. DW and WX are responsible for research supervision. All authors read and approved the final manuscript.

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Correspondence to Dan Wang or Wei Xiong.

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Xiang, P., Tang, L., Zhang, Y. et al. circSETD3 confers radiotherapy resistance in nasopharyngeal carcinoma by attenuating ER stress-induced autophagy and apoptosis via PDIA6 upregulation. Oncogene 45, 368–382 (2026). https://doi.org/10.1038/s41388-025-03652-1

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