Cisplatin inhibits SIRT3-deacetylation MTHFD2 to disturb cellular redox balance in colorectal cancer cell
Cisplatin inhibits SIRT3-deacetylation MTHFD2 to disturb cellular redox balance in colorectal cancer cell
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顺铂抑制 SIRT3-脱乙酰化 MTHFD2 扰乱结直肠癌细胞中的细胞氧化还原平衡
DOI：
10.1038/s41419-020-02825-y
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发表时间：
2020-08-06
影响因子：
9
通讯作者：
Yu, Wei
中科院分区：
文献类型：
--
作者：
Wan, Xingyou;Wang, Chao;Yu, Wei
叶酸偶联代谢酶MTHFD 2（线粒体亚甲基四氢叶酸脱氢酶/环化水解酶）赋予氧化还原稳态并驱动癌细胞增殖和迁移。在这里，我们表明MTHFD 2是高度乙酰化的，赖氨酸88是关键的乙酰化位点。SIRT 3是线粒体中主要的脱乙酰酶，负责MTHFD 2的脱乙酰化。有趣的是，化学治疗剂顺铂抑制SIRT 3的表达以诱导结直肠癌细胞中MTHFD 2的乙酰化。顺铂诱导的乙酰化K88 MTHFD 2足以抑制其酶活性并下调结直肠癌细胞中的NADPH水平。Ac-K88-MTHFD 2在人结直肠癌样品中显著降低，并且与SIRT 3的上调表达负相关。我们的研究结果揭示了cisplatin-SIRT 3-MTHFD 2在氧化还原稳态中的未知调节轴，并提出了通过靶向MTHFD 2进行癌症治疗的潜在治疗策略。
The folate-coupled metabolic enzyme MTHFD2 (the mitochondrial methylenetetrahydrofolate dehydrogenase/cyclohydrolase) confers redox homeostasis and drives cancer cell proliferation and migration. Here, we show that MTHFD2 is hyperacetylated and lysine 88 is the critical acetylated site. SIRT3, the major deacetylase in mitochondria, is responsible for MTHFD2 deacetylation. Interestingly, chemotherapeutic agent cisplatin inhibits expression of SIRT3 to induce acetylation of MTHFD2 in colorectal cancer cells. Cisplatin-induced acetylated K88 MTHFD2 is sufficient to inhibit its enzymatic activity and downregulate NADPH levels in colorectal cancer cells. Ac-K88-MTHFD2 is significantly decreased in human colorectal cancer samples and is inversely correlated with the upregulated expression of SIRT3. Our findings reveal an unknown regulation axis of cisplatin-SIRT3-MTHFD2 in redox homeostasis and suggest a potential therapeutic strategy for cancer treatments by targeting MTHFD2.