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RNF126-mediated ubiquitination of FSP1 affects its subcellular localization and ferroptosis

Oncogene (2024)Cite this article

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Abstract

Medulloblastoma (MB) is a prevalent malignant brain tumor among children, which can be classified into four primary molecular subgroups. Group 3 MB (G3-MB) is known to be highly aggressive and associated with a poor prognosis, necessitating the development of novel and effective therapeutic interventions. Ferroptosis, a regulated form of cell death induced by lipid peroxidation, has been identified as a natural tumor suppression mechanism in various cancers. Nevertheless, the potential role of ferroptosis in the treatment of G3-MB remains unexplored. In this study, we demonstrate that RNF126 acts as an anti-ferroptotic gene by interacting with ferroptosis suppressor protein 1 (FSP1, also known as AIFM2) and ubiquitinating FSP1 at the 4KR-2 sites. Additionally, the deletion of RNF126 reduces the subcellular localization of FSP1 in the plasma membrane, resulting in an increase in the CoQ/CoQH2 ratio in G3-MB. The RNF126-FSP1-CoQ10 pathway plays a pivotal role in suppressing phospholipid peroxidation and ferroptosis both in vivo and in vitro. Clinically, RNF126 exhibited elevated expression in G3-MB and its overexpression was significantly associated with reduced patient survival. Our findings indicate that RNF126 regulates G3-MB sensitivity to ferroptosis by ubiquitinating FSP1, which provides new evidence for the potential G3-MB therapy.

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Fig. 1: RNF126 regulates ferroptosis in G3-MB cells.
Fig. 2: RNF126 regulates ferroptosis sensitivity through altering membrane localization of FSP1.
Fig. 3: Identification of RNF126 as an E3 ubiquitin ligase that ubiquitinates FSP1.
Fig. 4: Mapping interacting domains in FSP1 and RNF126.
Fig. 5: Loss of RNF126 sensitizes medulloblastoma to ferroptosis in intracranial orthotopic tumor model.
Fig. 6: The expression level of RNF126 is significantly upregulated in G3-MB and correlates with unfavorable prognosis.

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Data availability

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

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Acknowledgements

We thank all participants and personnel involved in the study. We thank Professor Yujie Tang (Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China) for providing the D283 and D458 cells.

Funding

This research was supported by the National Key Research and Development Program of China (No. 2022YFC2705002 to JM), the National Natural Science Foundation of China (No. 8227102214 to JM) and Shanghai Leading Talent Program.

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  1. These authors contributed equally: Wanqun Xie, Jiajia Wang, Shuaiwei Tian.

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  1. Department of Pediatric Neurosurgery, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Wanqun Xie, Jiajia Wang, Shuaiwei Tian, Heng Zhao, Liangliang Cao, Zhuangzhuang Liang, Jian Yang, Yang Zhao, Baocheng Wang, Feng Jiang & Jie Ma

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Contributions

WX, JW, and ST performed the experiments, and prepared figures and tables. WX and JM co-wrote the manuscript. LC coordinated and oversaw the bioinformatics data analysis. LC, ST, JY, ZL, BW, YZ, QW, and FJ analyzed the data, collected samples or clinical data, and prepared figures. LC and JW guided the animal experiments.

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Correspondence to Jie Ma.

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Xie, W., Wang, J., Tian, S. et al. RNF126-mediated ubiquitination of FSP1 affects its subcellular localization and ferroptosis. Oncogene (2024). https://doi.org/10.1038/s41388-024-02949-x

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