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Silencing IKBKE inhibits the migration and invasion of glioblastoma by promoting Snail1 degradation

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Abstract

Purpose

Glioblastoma multiforme (GBM) is one of the most common malignant brain tumors in adults and has high mortality and relapse rates. Over the past few years, great advances have been made in the diagnosis and treatment of GBM, but unfortunately, the five-year overall survival rate of GBM patients is approximately 5.1%. Inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE) is a major oncogenic protein in tumors and can promote evil development of GBM. Snail1, a key inducer of the epithelial-mesenchymal transition (EMT) transcription factor, is subjected to ubiquitination and degradation, but the mechanism by which Snail1 is stabilized in tumors remains unclear. Our study aimed to investigate the mechanism of IKBKE regulating Snail1 in GBM.

Methods

First, we analyzed the correlation between the expression of IKBKE and the tumor grade and prognosis through public databases and laboratory specimen libraries. Second, immunohistochemistry (IHC) and western blot were used to detect the correlation between IKBKE and Snail expression in glioma samples and cell lines. Western blot and immunofluorescence (IF) experiments were used to detect the quality and distribution of IKBKE and Snail1 proteins. Third, In situ animal model of intracranial glioma to detect the regulatory effect of IKBKE on intracranial tumors.

Results

In this study, Our study reveals a new connection between IKBKE and Snail1, where IKBKE can directly bind to Snail1, translocate Snail1 into the nucleus from the cytoplasm. Downregulation of IKBKE results in Snail1 destabilization and impairs the tumor cell migration and invasion capabilities.

Conclusion

Our studies suggest that the IKBKE-Snail1 axis may serve as a potential therapeutic target for GBM treatment.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant NO.81572490).

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Author notes

  1. Y. Liu and G. Guo contributed equally to this study.

Authors and Affiliations

  1. Henan Provincial People’s Hospital, Cerebrovascular Disease Hospital, Zhengzhou, 450003, Henan, China

    Y. Liu, G. Guo, L. Zhao & C. Li

  2. Department of Neurosurgery, Zhengzhou University People’s Hospital, Zhengzhou, 450003, Henan, China

    Y. Liu, G. Guo, L. Zhao & C. Li

  3. Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China

    Y. Lu, X. Chen, X. Yang & Q. Huang

  4. Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin, China

    Y. Lu, X. Chen, X. Yang & Q. Huang

  5. Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, China

    Y. Lu, X. Chen, X. Yang & Q. Huang

  6. Department of Pathology, Zhengzhou University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou, 450003, Henan, China

    L. Zhu

  7. Department of Neurosurgery, Ningbo Hospital of Zhejiang University, Ningbo, 315000, Zhejiang, China

    Z. Zhang

  8. National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300052, China

    X. Jin

  9. Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China

    J. Dong

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  1. Y. Liu
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Correspondence to Q. Huang.

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All assays were performed in accordance with regulations and internal biosafety and bioethical guidelines of Tianjin Medical University and Tianjin Science and Technology Committee (No. IRB2019-WZ-129).

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12094_2021_2726_MOESM1_ESM.tif

Supplementary file 1: Figure 1. Transfected GBM cells were examined by fluorescence microscopy (left panel) and phase-contrast microscopy (right panel) (scale bar = 5 mm) (TIF 3696 KB).

12094_2021_2726_MOESM2_ESM.tif

Supplementary file 2: Figure 2. Expression of Snail1 in IKBKE-knockdown and overexpression cells was examined at the transcript level by qRT-PCR (TIF 914 KB).

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Liu, Y., Guo, G., Lu, Y. et al. Silencing IKBKE inhibits the migration and invasion of glioblastoma by promoting Snail1 degradation. Clin Transl Oncol 24, 816–828 (2022). https://doi.org/10.1007/s12094-021-02726-2

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