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Membrane flexibility induced by BST2 contributes to radioresistance in glioblastoma

Oncogene volume 44, pages 3816–3830 (2025)Cite this article

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Abstract

Glioblastoma (GBM) is an aggressive brain tumor with a poor prognosis due to its resistance to radiotherapy. Epidermal growth factor receptor variant III (EGFRvIII), a common mutation in GBM, promotes radioresistance through ligand-independent activation. We hypothesized that membrane flexibility influences EGFRvIII activation and enhances resistance. Bone marrow stromal antigen 2 (BST2, CD317, or TETHERIN) was identified as a key mediator linking membrane dynamics to EGFRvIII-driven survival signaling. Radiation-induced changes in membrane flexibility amplified BST2 activity, stabilizing lipid rafts and promoting EGFRvIII clustering. Pharmacological inhibition of BST2 with arbutin, an FDA-approved compound, disrupted this mechanism, increasing GBM radiosensitivity by enhancing mitochondrial reactive oxygen species (ROS) production and apoptosis. Additionally, BST2 downregulation impaired de novo lipogenesis and reduced lipid droplet accumulation, highlighting its role in metabolic reprogramming. In orthotopic xenograft models, BST2 inhibition suppressed tumor growth and prolonged survival. These findings establish BST2 as a key regulator of membrane-driven radioresistance in GBM. Targeting BST2-mediated membrane remodeling may provide a novel therapeutic strategy to enhance radiotherapy efficacy.

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Fig. 1: BST2 is upregulated in radioresistant GBM cells and radiation increases BST2 expression.
Fig. 2: BST2 downregulation suppresses radioresistance in GBM cells.
Fig. 3: Membrane flexibility by BST2 contributed to the activation of EGFRvIII.
Fig. 4: BST2 downregulation sensitizes to IR by increasing mitochondrial ROS.
Fig. 5: Pharmacological regulation of BST2 sensitizes GBM cells to IR.
Fig. 6: Arbutin attenuates tumor growth in GBM xenograft mouse models.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korean government (MSIT) (NRF-2022R1A2C1009681, HSY; RS-2023-00207904, BHY). This research was also supported by Global-Learning & Academic research institution for Master’s·PhD students, and Postdocs (LAMP) Program of the National Research Foundation of Korea (NRF) grant funded by the Ministry of Education (No. RS-2023-00301938).

Author information

Author notes

  1. Eunguk Shin

    Present address: Joonghun Pharmaceutical Co.Ltd, Seoul, 07236, Republic of Korea

Authors and Affiliations

  1. Department of Integrated Biological Science, Pusan National University, Busan, 46241, Republic of Korea

    Haksoo Lee, Dahye Kim, Byeongsoo Kim, Eunguk Shin & BuHyun Youn

  2. Institute for Future Earth, Pusan National University, Busan, 46241, Republic of Korea

    Haksoo Lee

  3. Department of Neurosurgery, Yale School of Medicine, New Haven, CT, 06510, USA

    Hyunkoo Kang

  4. Department of Naval Architecture and Ocean Engineering, Pusan National University, Busan, 46241, Republic of Korea

    Jae-Myung Lee

  5. Hydrogen Ship Technology Center, Pusan National University, Busan, 46241, Republic of Korea

    Jae-Myung Lee

  6. Department of Integrative Bioscience and Biotechnology, Sejong University, Seoul, 05006, Republic of Korea

    HyeSook Youn

  7. Nuclear Science Research Institute, Pusan National University, Busan, 46241, Republic of Korea

    BuHyun Youn

  8. Department of Biological Sciences, Pusan National University, Busan, 46241, Republic of Korea

    BuHyun Youn

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Contributions

Haksoo Lee: Formal analysis, Investigation, Writing – original draft. Dahye Kim: Validation, Investigation. Byeongsoo Kim: Validation, Investigation. Eunguk Shin: Validation. Hyunkoo Kang: Validation. Jae-Myung Lee: Resources. HyeSook Youn: Conceptualization, Investigation, Funding acquisition. BuHyun Youn: Conceptualization, Supervision, Funding acquisition, Writing - review & editing.

Corresponding author

Correspondence to BuHyun Youn.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

This study was approved by the Institutional Animal Care and Use Committee of Pusan National University (Approval Number: PNU-2022-0060) and adhered to the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Human GBM stem cell lines (BCL20-HP02 and BCL21-HP03) were obtained from surgical specimens under a protocol approved by the Institutional Review Board of Haeundae Paik Hospital, Inje University (Approval Number: HPIRB:2017-06-007). Written informed consent was obtained from all patients prior to tissue collection.

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Lee, H., Kim, D., Kim, B. et al. Membrane flexibility induced by BST2 contributes to radioresistance in glioblastoma. Oncogene 44, 3816–3830 (2025). https://doi.org/10.1038/s41388-025-03544-4

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