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Palmitoylation of MDH2 by ZDHHC18 activates mitochondrial respiration and accelerates ovarian cancer growth

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Abstract

Epithelial ovarian cancer (EOC) exhibits strong dependency on the tricarboxylic acid (TCA) cycle and oxidative phosphorylation to fuel anabolic process. Here, we show that malate dehydrogenase 2 (MDH2), a key enzyme of the TCA cycle, is palmitoylated at cysteine 138 (C138) residue, resulting in increased activity of MDH2. We next identify that ZDHHC18 acts as a palmitoyltransferase of MDH2. Glutamine deprivation enhances MDH2 palmitoylation by increasing the binding between ZDHHC18 and MDH2. MDH2 silencing represses mitochondrial respiration as well as ovarian cancer cell proliferation both in vitro and in vivo. Intriguingly, re-expression of wild-type MDH2, but not its palmitoylation-deficient C138S mutant, sustains mitochondrial respiration and restores the growth as well as clonogenic capability of ovarian cancer cells. Notably, MDH2 palmitoylation level is elevated in clinical cancer samples from patients with high-grade serous ovarian cancer. These observations suggest that MDH2 palmitoylation catalyzed by ZDHHC18 sustains mitochondrial respiration and promotes the malignancy of ovarian cancer, yielding possibilities of targeting ZDHHC18-mediated MDH2 palmitoylation in the treatment of EOC.

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Acknowledgements

This work was supported by the National Key Research and Development Program of China (2020YFA0803402 and 2019YFA0801703), the National Natural Science Foundation of China (81872240, 81802745, 81790250/81790253 and 91959202), and Innovation Program of Shanghai Municipal Education Commission (N173606). We thank members of the Lei Laboratory for discussion throughout this study. We also appreciate the Biomedical Core Facility of Fudan University for technical support.

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Authors and Affiliations

  1. Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; Shanghai Key Laboratory of Radiation Oncology; The Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College, Fudan University, Shanghai, 200032, China

    Xuan Pei, Kai-Yue Li, Yuan Shen, Jin-Tao Li, Ming-Zhu Lei, Cai-Yun Fang, Hao-Jie Lu, Wenyu Wen, Miao Yin, Jia Qu & Qun-Ying Lei

  2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China

    Xuan Pei, Kai-Yue Li, Yuan Shen, Jin-Tao Li, Ming-Zhu Lei, Cai-Yun Fang, Hao-Jie Lu, Hui-Juan Yang, Miao Yin, Jia Qu & Qun-Ying Lei

  3. Department of Gynecological Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China

    Xuan Pei & Hui-Juan Yang

  4. State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, 200032, China

    Wenyu Wen & Qun-Ying Lei

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  1. Xuan Pei
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Correspondence to Jia Qu or Qun-Ying Lei.

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Compliance and ethics The author(s) declare that they have no conflict of interest. The procedures related to human and animal subjects of our study were approved by Ethic Committee of Fudan University Shanghai Cancer Center and Ethics Committee of the Department of Laboratory Animals, Fudan University, China.

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Pei, X., Li, KY., Shen, Y. et al. Palmitoylation of MDH2 by ZDHHC18 activates mitochondrial respiration and accelerates ovarian cancer growth. Sci. China Life Sci. 65, 2017–2030 (2022). https://doi.org/10.1007/s11427-021-2048-2

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