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TRIM3 facilitates ferroptosis in non-small cell lung cancer through promoting SLC7A11/xCT K11-linked ubiquitination and degradation

Cell Death & Differentiation volume 31, pages 53–64 (2024)Cite this article

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Abstract

Ferroptosis, a unique form of regulated necrotic cell death, is caused by excessive iron-dependent lipid peroxidation. However, the underlying mechanisms driving ferroptosis in human cancers remain elusive. In this study, we identified TRIM3, an E3 ubiquitin-protein ligase, as a key regulator of ferroptosis. TRIM3 is downregulated in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), two major types of non-small cell lung cancer (NSCLC). Forced expression of TRIM3 promotes cell death by enhancing the cellular level of ROS and lipid peroxidation. Moreover, our in vivo study determined that TRIM3 overexpression diminishes the tumorigenicity of NSCLC cells, indicating that TRIM3 functions as a tumor suppressor in NSCLC. Mechanistically, TRIM3 directly interacts with SLC7A11/xCT through its NHL domain, leading to SCL7A11 K11-linked ubiquitination at K37, which promotes SLC7A11 proteasome-mediated degradation. Importantly, TRIM3 expression exhibits a negative correlation with SCL7A11 expression in clinical NSCLC samples, and low TRIM3 expression is associated with a worse prognosis. This study reveals that TRIM3 functions as a tumor suppressor that can impede the tumorigenesis of NSCLC by degrading SLC7A11, suggesting a novel therapeutic strategy against NSCLC.

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Fig. 1: TRIM3 is downregulated in non-small cell lung cancer.
Fig. 2: TRIM3 overexpression impedes the proliferation and invasion of lung cancer cells.
Fig. 3: TRIM3 facilitates ferroptosis in lung cancer cells.
Fig. 4: TRIM3 promotes xCT degradation.
Fig. 5: TRIM3 catalyzes K11-linked ubiquitination of xCT at K37.
Fig. 6: TRIM3 promotes ferroptosis in NSCLC cells through xCT.
Fig. 7: TRIM3 shows a negative correlation with xCT protein levels in clinical NSCLC samples.

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References

  1. Brody H. Lung cancer. Nature. 2020;587:S7.

    Article  CAS  PubMed  Google Scholar 

  2. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71:209–49.

    Article  PubMed  Google Scholar 

  3. Le X, Nilsson M, Goldman J, Reck M, Nakagawa K, Kato T, et al. Dual EGFR-VEGF pathway inhibition: a promising strategy for patients With EGFR-Mutant NSCLC. J Thorac Oncol. 2021;16:205–15.

    Article  CAS  PubMed  Google Scholar 

  4. Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature. 2018;553:446–54.

    Article  CAS  PubMed  Google Scholar 

  5. Wang M, Herbst RS, Boshoff C. Toward personalized treatment approaches for non-small-cell lung cancer. Nat Med. 2021;27:1345–56.

    Article  CAS  PubMed  Google Scholar 

  6. Abbosh C, Frankell AM, Harrison T, Kisistok J, Garnett A, Johnson L, et al. Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA. Nature. 2023;616:553–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72:7–33.

    Article  PubMed  Google Scholar 

  8. Jiang X, Stockwell BR, Conrad M. Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol. 2021;22:266–82.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Chen J, Li X, Ge C, Min J, Wang F. The multifaceted role of ferroptosis in liver disease. Cell Death Differ. 2022;29:467–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 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 

  11. Seibt TM, Proneth B, Conrad M. Role of GPX4 in ferroptosis and its pharmacological implication. Free Radic Biol Med. 2019;133:144–52.

    Article  CAS  PubMed  Google Scholar 

  12. Zhang H, Deng T, Liu R, Ning T, Yang H, Liu D, et al. CAF secreted miR-522 suppresses ferroptosis and promotes acquired chemo-resistance in gastric cancer. Mol Cancer. 2020;19:43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lei G, Zhuang L, Gan B. Targeting ferroptosis as a vulnerability in cancer. Nat Rev Cancer. 2022;22:381–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Yan HF, Zou T, Tuo QZ, Xu S, Li H, Belaidi AA, et al. Ferroptosis: mechanisms and links with diseases. Signal Transduct Target Ther. 2021;6:49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Koppula P, Zhuang L, Gan B. Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy. Protein Cell. 2021;12:599–620.

    Article  CAS  PubMed  Google Scholar 

  16. Dong H, Xia Y, Jin S, Xue C, Wang Y, Hu R, et al. Nrf2 attenuates ferroptosis-mediated IIR-ALI by modulating TERT and SLC7A11. Cell Death Dis. 2021;12:1027.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gao R, Kalathur RKR, Coto-Llerena M, Ercan C, Buechel D, Shuang S, et al. YAP/TAZ and ATF4 drive resistance to Sorafenib in hepatocellular carcinoma by preventing ferroptosis. EMBO Mol Med. 2021;13:e14351.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Badeaux AI, Shi Y. Emerging roles for chromatin as a signal integration and storage platform. Nat Rev Mol Cell Biol. 2013;14:211–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Liu T, Jiang L, Tavana O, Gu W. The deubiquitylase OTUB1 mediates ferroptosis via stabilization of SLC7A11. Cancer Res. 2019;79:1913–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Li WW, Nie Y, Yang Y, Ran Y, Luo WW, Xiong MG, et al. Ubiquitination of TLR3 by TRIM3 signals its ESCRT-mediated trafficking to the endolysosomes for innate antiviral response. Proc Natl Acad Sci USA. 2020;117:23707–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Yan Q, Sun W, Kujala P, Lotfi Y, Vida TA, Bean AJ. CART: an Hrs/actinin-4/BERP/myosin V protein complex required for efficient receptor recycling. Mol Biol Cell. 2005;16:2470–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhuang T, Wang B, Tan X, Wu L, Li X, Li Z, et al. TRIM3 facilitates estrogen signaling and modulates breast cancer cell progression. Cell Commun Signal. 2022;20:45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wang X, Zhang Y, Pei X, Guo G, Xue B, Duan X, et al. TRIM3 inhibits P53 signaling in breast cancer cells. Cancer Cell Int. 2020;20:559.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chen G, Kong J, Tucker-Burden C, Anand M, Rong Y, Rahman F, et al. Human Brat ortholog TRIM3 is a tumor suppressor that regulates asymmetric cell division in glioblastoma. Cancer Res. 2014;74:4536–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Li C, Tang Z, Zhang W, Ye Z, Liu F. GEPIA2021: integrating multiple deconvolution-based analysis into GEPIA. Nucleic Acids Res. 2021;49:W242–W246.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Su Z, Yang Z, Xu Y, Chen Y, Yu Q. Apoptosis, autophagy, necroptosis, and cancer metastasis. Mol Cancer. 2015;14:48.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Emdad L, Bhoopathi P, Talukdar S, Pradhan AK, Sarkar D, Wang XY, et al. Recent insights into apoptosis and toxic autophagy: the roles of MDA-7/IL-24, a multidimensional anti-cancer therapeutic. Semin Cancer Biol. 2020;66:140–54.

    Article  CAS  PubMed  Google Scholar 

  28. Levy JMM, Towers CG, Thorburn A. Targeting autophagy in cancer. Nat Rev Cancer. 2017;17:528–42.

    Article  CAS  PubMed  Google Scholar 

  29. Li D, Li Y. The interaction between ferroptosis and lipid metabolism in cancer. Signal Transduct Target Ther. 2020;5:108.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Xie Y, Wang B, Zhao Y, Tao Z, Wang Y, Chen G, et al. Mammary adipocytes protect triple-negative breast cancer cells from ferroptosis. J Hematol Oncol. 2022;15:72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hornbeck PV, Zhang B, Murray B, Kornhauser JM, Latham V, Skrzypek E. PhosphoSitePlus, 2014: mutations, PTMs and recalibrations. Nucleic Acids Res. 2015;43:D512–520.

    Article  CAS  PubMed  Google Scholar 

  32. Tong X, Tang R, Xiao M, Xu J, Wang W, Zhang B, et al. Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research. J Hematol Oncol. 2022;15:174.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Jia X, Zhao C, Zhao W. Emerging roles of MHC class I region-encoded E3 ubiquitin ligases in innate immunity. Front Immunol. 2021;12:687102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Chao J, Zhang XF, Pan QZ, Zhao JJ, Jiang SS, Wang Y, et al. Decreased expression of TRIM3 is associated with poor prognosis in patients with primary hepatocellular carcinoma. Med Oncol. 2014;31:102.

    Article  PubMed  Google Scholar 

  35. Liu Y, Raheja R, Yeh N, Ciznadija D, Pedraza AM, Ozawa T, et al. TRIM3, a tumor suppressor linked to regulation of p21(Waf1/Cip1.). Oncogene. 2014;33:308–15.

    Article  CAS  PubMed  Google Scholar 

  36. Yan J, Wan P, Choksi S, Liu ZG. Necroptosis and tumor progression. Trends Cancer. 2022;8:21–27.

    Article  CAS  PubMed  Google Scholar 

  37. Levine B, Kroemer G. Biological functions of autophagy genes: a disease perspective. Cell. 2019;176:11–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Maremonti F, Meyer C, Linkermann A. Mechanisms and models of kidney tubular necrosis and nephron loss. J Am Soc Nephrol. 2022;33:472–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhou B, Liu J, Kang R, Klionsky DJ, Kroemer G, Tang D. Ferroptosis is a type of autophagy-dependent cell death. Semin Cancer Biol. 2020;66:89–100.

    Article  CAS  PubMed  Google Scholar 

  40. Mou Y, Wang J, Wu J, He D, Zhang C, Duan C, et al. Ferroptosis, a new form of cell death: opportunities and challenges in cancer. J Hematol Oncol. 2019;12:34.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Sui S, Xu S, Pang D. Emerging role of ferroptosis in breast cancer: new dawn for overcoming tumor progression. Pharm Ther. 2022;232:107992.

    Article  CAS  Google Scholar 

  42. Wang X, Chen Y, Wang X, Tian H, Wang Y, Jin J, et al. Stem cell factor SOX2 confers ferroptosis resistance in lung cancer via upregulation of SLC7A11. Cancer Res. 2021;81:5217–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Yang J, Zhou Y, Xie S, Wang J, Li Z, Chen L, et al. Metformin induces ferroptosis by inhibiting UFMylation of SLC7A11 in breast cancer. J Exp Clin Cancer Res. 2021;40:206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ouyang S, Li H, Lou L, Huang Q, Zhang Z, Mo J, et al. Inhibition of STAT3-ferroptosis negative regulatory axis suppresses tumor growth and alleviates chemoresistance in gastric cancer. Redox Biol. 2022;52:102317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Shen L, Zhang J, Zheng Z, Yang F, Liu S, Wu Y, et al. PHGDH inhibits ferroptosis and promotes malignant progression by upregulating SLC7A11 in bladder cancer. Int J Biol Sci. 2022;18:5459–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Liu J, Xia X, Huang P. xCT: a critical molecule that links cancer metabolism to redox signaling. Mol Ther. 2020;28:2358–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Chen X, Kang R, Kroemer G, Tang D. Broadening horizons: the role of ferroptosis in cancer. Nat Rev Clin Oncol. 2021;18:280–96.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The mechanistic scheme of this study was drawn using Figdraw (www.figdraw.com).

Funding

This work was supported by the “333 projects” of Jiangsu Province (grant numbers: BRA2020190).

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Author notes

  1. These authors contributed equally: Zhangjie Wang, Na Shen, Ziao Wang.

Authors and Affiliations

  1. Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China

    Zhangjie Wang, Yang Wang & Yu Liu

  2. Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China

    Na Shen

  3. Department of Cardiothoracic Surgery, First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, China

    Ziao Wang

  4. Department of Oncology, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, 225300, China

    Lei Yu, Song Yang, Gaohua Han & Qi Zhang

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Contributions

Conception and design: ZJW; data acquisition, analysis, and interpretation: ZJW, NS; investigation: LY, SY, YW, and YL; acquisition of patient specimens: QZ and GHH; article drafting and revising: ZJW; and article writing: ZJW. All authors approved the final version of the manuscript.

Corresponding authors

Correspondence to Gaohua Han or Qi Zhang.

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The authors declare that they have no competing interests.

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All participants provided informed consent. All human tissue research in this study had the approval of ethics committees of the Affiliated Taizhou People’s Hospital of Nanjing Medical University (Taizhou, China) and Shanghai Outdo Biotech (Shanghai, China). All of the animal experiments were performed by the relevant guidelines and regulations and were approved by the Institutional Animal Care and Use Committee (IACUC) of Nanjing Medical University.

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Wang, Z., Shen, N., Wang, Z. et al. TRIM3 facilitates ferroptosis in non-small cell lung cancer through promoting SLC7A11/xCT K11-linked ubiquitination and degradation. Cell Death Differ 31, 53–64 (2024). https://doi.org/10.1038/s41418-023-01239-5

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