Palmitoylation of MDH2 by ZDHHC18 activates mitochondrial respiration and accelerates ovarian cancer growth
Palmitoylation of MDH2 by ZDHHC18 activates mitochondrial respiration and accelerates ovarian cancer growth
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ZDHHC18 对 MDH2 的棕榈酰化可激活线粒体呼吸并加速卵巢癌的生长
DOI：
10.1007/s11427-021-2048-2
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发表时间：
2022-03-25
影响因子：
9.1
通讯作者：
Qun-Ying Lei
中科院分区：
文献类型：
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作者：
Pei, Xuan;Kai-Yue Li;Qun-Ying Lei
上皮性卵巢癌（EOC）对三羧酸（TCA）循环和氧化磷酸化具有很强的依赖性，以促进合成代谢过程。在这里，我们表明，苹果酸脱氢酶2（MDH2），TCA循环的关键酶，是棕榈酰化的半胱氨酸138（C138）残基，导致MDH2的活性增加。我们接下来确定ZDHHC18作为MDH2的棕榈酰转移酶。谷氨酰胺缺乏通过增加ZDHHC18和MDH2之间的结合增强MDH2棕榈酰化。MDH2沉默抑制线粒体呼吸以及体外和体内卵巢癌细胞增殖。有趣的是，野生型MDH2的重新表达，而不是其棕榈酰化缺陷的C138S突变体，维持线粒体呼吸，恢复卵巢癌细胞的生长和克隆形成能力。值得注意的是，来自高级别浆液性卵巢癌患者的临床癌症样本中MDH 2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，从而产生靶向ZDHHC18介导的MDH2棕榈酰化治疗EOC的可能性。
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.MDH2silencing represses mitochondrial respiration as well as ovarian cancer cell proliferation bothin vitroandin 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.