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Synthetic lethality through Gsk3β inhibition in glioma stem cells via the WNT-WWC1-YAP axis

Oncogene volume 44, pages 2427–2439 (2025)Cite this article

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Abstract

Glioblastoma (GBM) is an aggressive brain tumor driven by glioma stem cells (GSCs), which contribute to tumor growth and therapeutic resistance. This study investigates the effects of Gsk3β inhibition on GSC viability, focusing on the role of the canonical WNT signaling pathway. We found that Gsk3β inhibition activates the WNT pathway, leading to upregulation of Wwc1, which downregulates Yap via Lats1 phosphorylation. This reduces GSC proliferation, self-renewal, and enhances chemosensitivity. Analysis of clinical datasets revealed that WNT pathway activation correlates with improved prognosis in proneural gliomas, particularly in IDH1-mutated tumors. Our findings suggest that targeting the WNT-WWC1-YAP axis, particularly through Gsk3β inhibition, could induce synthetic lethality in GSCs and provide a promising therapeutic strategy for gliomas. These results highlight the potential of exploiting WNT-induced synthetic lethality as a novel approach for glioma treatment.

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Fig. 1: The GSK3 inhibitor CHIR inhibits GSC growth and induce cell death.
Fig. 2: Gsk3β but not Gsk3α regulates the proliferation, self-renewal and tumorigenesis capacity of mouse GSCs (HTS).
Fig. 3: Activation of canonical WNT signaling affects the growth of HTS cells and their sensitivity to CHIR treatment.
Fig. 4: Activation of the canonical WNT signaling pathway in human gliomas is associated with proneural/G-CIMP subtypes and better prognosis.
Fig. 5: Activation of Wwc1 expression is the downstream effect of CHIR treatment.
Fig. 6: The Lats-Yap axis is the target of Gsk3β inhibition by CHIR.
Fig. 7: Yap modulates glioma cell proliferation, self-renewal and sensitivity to chemotherapeutic agents.
Fig. 8: The Gsk3β inhibitor alsterpaullone (ALP) inhibits glioma growth in vitro and in vivo.

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Acknowledgements

The authors thank Dr. Wei Mo for HTS cells and Dr. Shangfeng Gao for GBM paraffin sections. This work was funded by the National Key Research and Development Program of China (#2022YFA1103900 to JC), the Changping Laboratory and the CAMS Innovation Fund for Medical Sciences (CIFMS) (#2024-I2M-3-022 to JC). Additional funds to JC are from the Chinese Institute for Brain Research and Changping Laboratory.

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Author notes

  1. These authors contributed equally: Fangfang Ren, Yulan Yi, Ting Lu, Xinze Liu.

Authors and Affiliations

  1. National Institute of Biological Sciences, Beijing, China

    Fangfang Ren & Song Huang

  2. Institute of Functional Nano and Soft Materials (FUNSOM) & Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou, China

    Yulan Yi & Jian Chen

  3. Department of Neurosurgery, First affiliated Hospital of Soochow University, Suzhou, China

    Ting Lu & Gang Cui

  4. Beijing Institute for Brain Research, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

    Xinze Liu & Jian Chen

  5. Chinese Institute for Brain Research, Beijing, Beijing, China

    Xinze Liu & Jian Chen

  6. Brain Tumor Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Luis F. Parada

  7. Changping Laboratory, Beijing, China

    Jian Chen

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Contributions

FFR, XZL, TL, YLY, GC and SH performed the experiments. JC designed the experiments. FFR, LFP and JC analyzed the data and wrote the paper. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Luis F. Parada or Jian Chen.

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All the experimental procedures were performed in compliance with the protocols approved by the Institutional Animal Care and Use Committee (IACUC) of Soochow University or the Chinese Institute for Brain Research. All mouse experiments were approved by and performed according to the institutional guidelines.

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Ren, F., Yi, Y., Lu, T. et al. Synthetic lethality through Gsk3β inhibition in glioma stem cells via the WNT-WWC1-YAP axis. Oncogene 44, 2427–2439 (2025). https://doi.org/10.1038/s41388-025-03418-9

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