Metformin regulates global DNA methylation via mitochondrial one-carbon metabolism
Metformin regulates global DNA methylation via mitochondrial one-carbon metabolism
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DOI：
10.1038/onc.2017.367
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发表时间：
2018-02-15
期刊：
影响因子：
8
通讯作者：
Menendez, J. A.
中科院分区：
文献类型：
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作者：
Cuyas, E.;Fernandez-Arroyo, S.;Menendez, J. A.
抗糖尿病药物二甲双胍可能通过调节表观基因组的代谢起到促进健康的作用。在这里，我们发现，二甲双胍通过降低S同型半胱氨酸甲基化，促进细胞甲基化，同时促进细胞甲基化的普遍甲基供体，同时促进腺苷甲硫氨酸的积累。通过在野生型和AMP激活的蛋白激酶(AMPK)、丝氨酸羟甲基转移酶2(SHMT2)和MCI缺失的实验对细胞中使用二甲双胍和线粒体/复合体I(MCI)靶向的二甲双胍类似物(NorMitoMet)，我们提供了证据，表明二甲双胍通过靶向丝氨酸线粒体一碳流量与CI活性之间的偶联来增加SAM：SAH比率相关的甲基化能力。通过增加叶酸储存中一碳单位对SAM的贡献，同时降低SAH以响应AMPK感应的能量危机，二甲双胍可以作为代谢-表观遗传调节因子，能够对连接细胞代谢和DNA甲基化机制的关键通道之一进行重新编程。
The anti-diabetic biguanide metformin may exert health-promoting effects via metabolic regulation of the epigenome. Here we show that metformin promotes global DNA methylation in non-cancerous, cancer-prone and metastatic cancer cells by decreasing S-adenosylhomocysteine (SAH), a strong feedback inhibitor of S-adenosylmethionine (SAM)-dependent DNA methyltransferases, while promoting the accumulation of SAM, the universal methyl donor for cellular methylation. Using metformin and a mitochondria/complex I (mCI)-targeted analog of metformin (norMitoMet) in experimental pairs of wild-type and AMP-activated protein kinase (AMPK)-, serine hydroxymethyltransferase 2 (SHMT2)- and mCI-null cells, we provide evidence that metformin increases the SAM: SAH ratio-related methylation capacity by targeting the coupling between serine mitochondrial one-carbon flux and CI activity. By increasing the contribution of one-carbon units to the SAM from folate stores while decreasing SAH in response to AMPK-sensed energetic crisis, metformin can operate as a metabolo-epigenetic regulator capable of reprogramming one of the key conduits linking cellular metabolism to the DNA methylation machinery.