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
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.
Sci China Life Sci. 2022 Oct;65(10):2017-2030. doi: 10.1007/s11427-021-2048-2. Epub 2022 Mar 25.
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.
上皮性卵巢癌（EOC）对三羧酸（TCA）循环和氧化磷酸化表现出强烈依赖性，以驱动合成代谢过程。在此，我们表明苹果酸脱氢酶2（MDH2）作为TCA循环的关键酶，在半胱氨酸138（C138）残基处发生棕榈酰化，导致MDH2活性增加。接下来，我们鉴定出ZDHHC18作为MDH2的棕榈酰转移酶。谷氨酰胺剥夺通过增加ZDHHC18与MDH2之间的结合来增强MDH2棕榈酰化。MDH2沉默在体外和体内均抑制线粒体呼吸以及卵巢癌细胞增殖。有趣的是，野生型MDH2的重新表达而非其棕榈酰化缺陷型C138S突变体的重新表达可维持线粒体呼吸，并恢复卵巢癌细胞的生长以及克隆形成能力。值得注意的是，在高级别浆液性卵巢癌患者的临床癌症样本中，MDH2棕榈酰化水平升高。这些观察结果表明，由ZDHHC18催化的MDH2棕榈酰化维持线粒体呼吸并促进卵巢癌的恶性程度，为在EOC治疗中靶向ZDHHC18介导的MDH2棕榈酰化提供了可能性。
