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:

TRIM25 promotes temozolomide resistance in glioma by regulating oxidative stress and ferroptotic cell death via the ubiquitination of keap1

Oncogene volume 42, pages 2103–2112 (2023)Cite this article

Subjects

Abstract

Resistance to temozolomide (TMZ) remains an important cause of treatment failure in patients with glioblastoma multiforme (GBM). TRIM25, as a tripartite motif-containing (TRIM) family member, plays a significant role in cancer progression and chemoresistance. However, the function of TRIM25 and its precise mechanism in regulating GBM progression and TMZ resistance remain poorly understood. We found that the expression of TRIM25 was upregulated in GBM, and it was associated with tumor grade and TMZ resistance. Elevated TRIM25 expression predicted a poor prognosis in GBM patients and enhanced tumor growth in vitro and in vivo. Further analysis revealed that elevated TRIM25 expression inhibited oxidative stress and ferroptotic cell death in glioma cells under TMZ treatment. Mechanistically, TRIM25 regulates TMZ resistance by promoting the nuclear import of nuclear factor erythroid 2-related factor 2(Nrf2) via keap1 ubiquitination. Knockdown of Nrf2 abolished the ability of TRIM25 to promote glioma cell survival and TMZ resistance. Our results support the targeting of TRIM25 as a new therapeutic strategy for glioma.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: TRIM25 expression and its correlation with clinical features of glioma.
Fig. 2: TRIM25 promotes TMZ resistance in glioma cells.
Fig. 3: TRIM25 regulates TMZ resistance via ROS-driven ferroptosis.
Fig. 4: TRIM25 alleviates ROS accumulation by activating Nrf2.
Fig. 5: TRIM25 regulates TMZ chemoresistance in glioma cells in an Nrf2-dependent manner.
Fig. 6: TRIM25 promotes the nuclear import of Nrf2 by ubiquitinating Keap1.
Fig. 7: TRIM25 promoted TMZ resistance in an orthotopic GBM model in vivo.

Similar content being viewed by others

Data availability

All relevant data are available in the main text or the Supplementary Materials.

References

  1. Tiek DM, Erdogdu B, Razaghi R, Jin L, Sadowski N, Alamillo-Ferrer C, et al. Temozolomide-induced guanine mutations create exploitable vulnerabilities of guanine-rich DNA and RNA regions in drug-resistant gliomas. Sci Adv. 2022;8:eabn3471.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ostrom QT, Cioffi G, Waite K, Kruchko C, Barnholtz-Sloan JS. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2014-8. Neuro Oncol. 2021;23:iii1–iii105.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Nizamutdinov D, Stock EM, Dandashi JA, Vasquez EA, Mao Y, Dayawansa S, et al. Prognostication of survival outcomes in patients diagnosed with glioblastoma. World Neurosurg. 2018;109:e67–74.

    Article  PubMed  Google Scholar 

  4. Messaoudi K, Clavreul A, Lagarce F. Toward an effective strategy in glioblastoma treatment. Part I: resistance mechanisms and strategies to overcome resistance of glioblastoma to temozolomide. Drug Discov Today. 2015;20:899–905.

    Article  CAS  PubMed  Google Scholar 

  5. Mannas JP, Lightner DD, Defrates SR, Pittman T, Villano JL. Long-term treatment with temozolomide in malignant glioma. J Clin Neurosci. 2014;21:121–3.

    Article  CAS  PubMed  Google Scholar 

  6. de Souza I, Monteiro LKS, Guedes CB, Silva MM, Andrade-Tomaz M, Contieri B, et al. High levels of NRF2 sensitize temozolomide-resistant glioblastoma cells to ferroptosis via ABCC1/MRP1 upregulation. Cell Death Dis. 2022;13:591.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Wei J, Wang Z, Wang W, Liu X, Wan J, Yuan Y, et al. Oxidative stress activated by sorafenib alters the temozolomide sensitivity of human glioma cells through autophagy and JAK2/STAT3-AIF axis. Front Cell Dev Biol. 2021;9:660005.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Liu Y, Liu K, Huang Y, Sun M, Tian Q, Zhang S, et al. TRIM25 promotes TNF-alpha-induced NF-kappaB activation through potentiating the K63-linked ubiquitination of TRAF2. J Immunol. 2020;204:1499–507.

    Article  CAS  PubMed  Google Scholar 

  9. Zhou S, Peng J, Xiao L, Zhou C, Fang Y, Ou Q, et al. TRIM25 regulates oxaliplatin resistance in colorectal cancer by promoting EZH2 stability. Cell Death Dis. 2021;12:463.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mei P, Xie F, Pan J, Wang S, Gao W, Ge R, et al. E3 ligase TRIM25 ubiquitinates RIP3 to inhibit TNF induced cell necrosis. Cell Death Differ. 2021;28:2888–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Liu Y, Tao S, Liao L, Li Y, Li H, Li Z, et al. TRIM25 promotes the cell survival and growth of hepatocellular carcinoma through targeting Keap1-Nrf2 pathway. Nat Commun. 2020;11:348.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017;45:W98–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhao Z, Zhang KN, Wang Q, Li G, Zeng F, Zhang Y, et al. Chinese Glioma Genome Atlas (CGGA): a comprehensive resource with functional genomic data from Chinese glioma patients. Genomics Proteomics Bioinformatics. 2021;19:1–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. He C, Lu S, Wang XZ, Wang CC, Wang L, Liang SP, et al. FOXO3a protects glioma cells against temozolomide-induced DNA double strand breaks via promotion of BNIP3-mediated mitophagy. Acta Pharmacol Sin. 2021;42:1324–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Fan P, Xie XH, Chen CH, Peng X, Zhang P, Yang C, et al. Molecular regulation mechanisms and interactions between reactive oxygen species and mitophagy. DNA Cell Biol. 2019;38:10–22.

    Article  CAS  PubMed  Google Scholar 

  16. Gao M, Yi J, Zhu J, Minikes AM, Monian P, Thompson CB, et al. Role of mitochondria in ferroptosis. Mol Cell. 2019;73:354–63.e3.

    Article  CAS  PubMed  Google Scholar 

  17. Gan B. Mitochondrial regulation of ferroptosis. J Cell Biol. 2021;220:e202105043.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Meng C, Zhan J, Chen D, Shao G, Zhang H, Gu W, et al. The deubiquitinase USP11 regulates cell proliferation and ferroptotic cell death via stabilization of NRF2 USP11 deubiquitinates and stabilizes NRF2. Oncogene. 2021;40:1706–20.

    Article  CAS  PubMed  Google Scholar 

  19. Sun X, Ou Z, Chen R, Niu X, Chen D, Kang R, et al. Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology. 2016;63:173–84.

    Article  CAS  PubMed  Google Scholar 

  20. Roh JL, Kim EH, Jang H, Shin D. Nrf2 inhibition reverses the resistance of cisplatin-resistant head and neck cancer cells to artesunate-induced ferroptosis. Redox Biol. 2017;11:254–62.

    Article  CAS  PubMed  Google Scholar 

  21. Hatakeyama S. TRIM proteins and cancer. Nat Rev Cancer. 2011;11:792–804.

    Article  CAS  PubMed  Google Scholar 

  22. Chen L, Yang X. TRIM11 cooperates with HSF1 to suppress the anti-tumor effect of proteotoxic stress drugs. Cell Cycle. 2019;18:60–8.

    Article  CAS  PubMed  Google Scholar 

  23. Chen L, Brewer MD, Guo L, Wang R, Jiang P, Yang X. Enhanced degradation of misfolded proteins promotes tumorigenesis. Cell Rep. 2017;18:3143–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kansanen E, Kuosmanen SM, Leinonen H, Levonen AL. The Keap1-Nrf2 pathway: mechanisms of activation and dysregulation in cancer. Redox Biol. 2013;1:45–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wei JW, Cui JQ, Zhou X, Fang C, Tan YL, Chen LY, et al. F25P preproinsulin abrogates the secretion of pro-growth factors from EGFRvIII cells and suppresses tumor growth in an EGFRvIII/wt heterogenic model. Cancer Lett. 2016;380:1–9.

    Article  CAS  PubMed  Google Scholar 

  26. Wong D, Sogerer L, Lee SS, Wong V, Lum A, Levine AB, et al. TRIM25 promotes Capicua degradation independently of ERK in the absence of ATXN1L. BMC Biol. 2020;18:154.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Takayama KI, Suzuki T, Tanaka T, Fujimura T, Takahashi S, Urano T, et al. TRIM25 enhances cell growth and cell survival by modulating p53 signals via interaction with G3BP2 in prostate cancer. Oncogene. 2018;37:2165–80.

    Article  CAS  PubMed  Google Scholar 

  28. Gack MU, Shin YC, Joo CH, Urano T, Liang C, Sun L, et al. TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity. Nature. 2007;446:916–20.

    Article  CAS  PubMed  Google Scholar 

  29. Yang Z, Wang J, He B, Zhang X, Li X, Kuang E. RTN3 inhibits RIG-I-mediated antiviral responses by impairing TRIM25-mediated K63-linked polyubiquitination. Elife. 2021;10:e68958.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bao Z, Hua L, Ye Y, Wang D, Li C, Xie Q, et al. MEF2C silencing downregulates NF2 and E-cadherin and enhances Erastin-induced ferroptosis in meningioma. Neuro Oncol. 2021;23:2014–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Li H, Yu Y, Liu Y, Luo Z, Law BYK, Zheng Y, et al. Ursolic acid enhances the antitumor effects of sorafenib associated with Mcl-1-related apoptosis and SLC7A11-dependent ferroptosis in human cancer. Pharmacol Res. 2022;182:106306.

    Article  CAS  PubMed  Google Scholar 

  32. Moujalled D, Southon AG, Saleh E, Brinkmann K, Ke F, Iliopoulos M, et al. BH3 mimetic drugs cooperate with Temozolomide, JQ1 and inducers of ferroptosis in killing glioblastoma multiforme cells. Cell Death Differ. 2022;29:1335–48.

    Article  CAS  PubMed  Google Scholar 

  33. Feng H, Liu Y, Gan Y, Li M, Liu R, Liang Z, et al. AdipoR1 regulates ionizing radiation-induced ferroptosis in HCC cells through Nrf2/xCT pathway. Oxid Med Cell Longev. 2022;2022:8091464.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Ma L, Wei J, Wan J, Wang W, Wang L, Yuan Y, et al. Low glucose and metformin-induced apoptosis of human ovarian cancer cells is connected to ASK1 via mitochondrial and endoplasmic reticulum stress-associated pathways. J Exp Clin Cancer Res. 2019;38:77.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Wan J, Liu H, Yang L, Ma L, Liu J, Ming L. JMJD6 promotes hepatocellular carcinoma carcinogenesis by targeting CDK4. Int J Cancer. 2019;144:2489–500.

    Article  CAS  PubMed  Google Scholar 

  36. Deng X, Lin N, Fu J, Xu L, Luo H, Jin Y, et al. The Nrf2/PGC1alpha pathway regulates antioxidant and proteasomal activity to alter cisplatin sensitivity in ovarian cancer. Oxid Med Cell Longev. 2020;2020:4830418.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Sun T, Mao W, Peng H, Wang Q, Jiao L. YAP promotes sorafenib resistance in hepatocellular carcinoma by upregulating survivin. Cell Oncol (Dordr). 2021;44:689–99.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This project was supported by the National Natural Science Foundation of China (No. 82002751), Medical Science and Technology Project of Henan Province (No. SBGJ202102139), China Postdoctoral Science Foundation (2020M682361), Excellent Youth Foundation of Henan Province (222300420071), Outstanding Young Talents of Health Science and Technology Innovation of Henan Province (YXKC2022033) and the Funding for Scientific Research and Innovation Team of The First Affiliated Hospital of Zhengzhou University (Grant No. QNCXTD2023005).

Author information

Author notes

  1. These authors contributed equally: Jianwei Wei, Li Wang, Yuyan Zhang.

Authors and Affiliations

  1. Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China

    Jianwei Wei, Yuyan Zhang & Xianzhi Liu

  2. Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China

    Li Wang

  3. Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China

    Ting Sun, Cai Zhang, Zhonglan Hu, Junhu Wan & Liwei Ma

  4. Key Clinical Laboratory of Henan province, Zhengzhou, 450052, China

    Ting Sun, Cai Zhang, Zhonglan Hu, Junhu Wan & Liwei Ma

  5. Electron Microscopy Laboratory of Renal Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China

    Lijuan Zhou

Authors
  1. Jianwei Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Li Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuyan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ting Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cai Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhonglan Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lijuan Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xianzhi Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Junhu Wan
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Liwei Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

LWM and JHW designed the study, and JWW, LW, and YYZ wrote the manuscript and performed the experiments. TS and CZ generated the figures, and ZLH, LJZ, and XZL revised the manuscript.

Corresponding authors

Correspondence to Junhu Wan or Liwei Ma.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval

Ethics approval and consent to participate in all experiments were performed in accordance with the standards of the ethics committee of the First Affiliated Hospital of Zhengzhou 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

Wei, J., Wang, L., Zhang, Y. et al. TRIM25 promotes temozolomide resistance in glioma by regulating oxidative stress and ferroptotic cell death via the ubiquitination of keap1. Oncogene 42, 2103–2112 (2023). https://doi.org/10.1038/s41388-023-02717-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-023-02717-3

Search

Advanced search

Quick links