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CircVPS8 promotes the malignant phenotype and inhibits ferroptosis of glioma stem cells by acting as a scaffold for MKRN1, SOX15 and HNF4A

Oncogene volume 43, pages 2679–2695 (2024)Cite this article

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Abstract

Exciting breakthroughs have been achieved in the field of glioblastoma with therapeutic interventions targeting specific ferroptosis targets. Nonetheless, the precise mechanisms through which circRNAs regulate the ferroptosis pathway have yet to be fully elucidated. Here we have identified a novel circRNA, circVPS8, which is highly expressed in glioblastoma. Our findings demonstrated that circVPS8 enhances glioma stem cells’ viability, proliferation, sphere-forming ability, and stemness. Additionally, it inhibits ferroptosis in GSCs. In vivo, experiments further supported the promotion of glioblastoma growth by circVPS8. Mechanistically, circVPS8 acts as a scaffold, binding to both MKRN1 and SOX15, thus facilitating the ubiquitination of MKRN1 and subsequent degradation of SOX15. Due to competitive binding, the ubiquitination ability of MKRN1 towards HNF4A is reduced, leading to elevated HNF4A expression. Increased HNF4A expression, along with decreased SOX15 expression, synergistically inhibits ferroptosis in glioblastoma. Overall, our study highlights circVPS8 as a promising therapeutic target and provides valuable insights for clinically targeted therapy of glioblastoma.

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Fig. 1: CircVPS8 is up-regulated in glioma tissues and correlated with the progression and poor prognosis.
Fig. 2: CircVPS8 promotes the proliferation and stemness of GSCs in vitro and in vivo.
Fig. 3: CircVPS8 protects glioma stem cells from ferroptotic cell death.
Fig. 4: CircVPS8 directly binds to SOX15 and down-regulates its expression.
Fig. 5: MKRN1 is essential for the degradation of SOX15 in GBM cells.
Fig. 6: CircVPS8 scaffolds MKRN1 binding to and ubiquitination degradation of SOX15.
Fig. 7: CircVPS8 upregulate HNF4A expression via inhibiting MKRN1 mediated ubiquitination degradation of HNF4A.
Fig. 8: CircVPS8 protects glioma stem cells from ferroptotic cell death via upregulating HNF4A.

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All the data obtained for the study could be available by inquiring the corresponding author.

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Acknowledgements

We would like to acknowledge our lab colleagues for their support in the development of this article.

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  1. These authors contributed equally: Jinpeng Hu, Xinqiao Li, Kai Xu.

Authors and Affiliations

  1. Department of Neurosurgery, The First Hospital of China Medical University, NO.155 North Nanjing Street, Shenyang, Liaoning, 110001, China

    Jinpeng Hu, Xinqiao Li, Kai Xu, Junhua Chen, Shengliang Zong, Hao Li, Guoqing Zhang, Zhengting Guo, Xiang Zhao & Zhitao Jing

  2. Department of Neurosurgery, The Central Hospital of Dalian University of Technology, Dalian, Liaoning, 116000, China

    Kai Xu

  3. International Education College, Liaoning University of Traditional Chinese Medicine, NO. 79 Chongshan East Road, Shenyang, Liaoning, 110042, China

    Haiying Zhang

  4. Department of Neurosurgery, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, 200072, China

    Yang Jiang

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Contributions

ZTJ and YJ conceived and designed the study; JPH, XQL and KX performed the experiments and wrote the manuscript; JHC, HYZ, SLZ, and HL collected and analyzed the data. GQZ, ZTG, and XZ contributed equally to this work. All authors read and approved the final version of the manuscript.

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Hu, J., Li, X., Xu, K. et al. CircVPS8 promotes the malignant phenotype and inhibits ferroptosis of glioma stem cells by acting as a scaffold for MKRN1, SOX15 and HNF4A. Oncogene 43, 2679–2695 (2024). https://doi.org/10.1038/s41388-024-03116-y

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