Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Science China. Life sciences, 2022-10, Vol.65 (10), p.2017-2030

Ort / Verlag

Beijing: Science China Press

Erscheinungsjahr

2022

Quelle

SpringerNature Journals

Beschreibungen/Notizen

• 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.