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

Apr 4, 2022

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

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

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.
© 2022. Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature.

Author

admin

View all posts

About The Expert

Xuan Pei

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.

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

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

Kai-Yue Li

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.

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

Yuan Shen

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.

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

Jin-Tao Li

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.

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

Ming-Zhu Lei

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.

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

Cai-Yun Fang

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.

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

Hao-Jie Lu

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.

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

Hui-Juan Yang

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

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

Wenyu Wen

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.

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

Miao Yin

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.

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

Jia Qu

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. jqu@fudan.edu.cn.

Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. jqu@fudan.edu.cn.

Qun-Ying Lei

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. qlei@fudan.edu.cn.

Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. qlei@fudan.edu.cn.

State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, 200032, China. qlei@fudan.edu.cn.

References

PubMed