ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism & Cancer Group, Catalan Institute of Oncology, Girona, Catalonia, Spain.
Girona Biomedical Research Institute (IDIBGI), Girona, Catalonia, Spain.
Oncogene. 2018 Feb 15;37(7):963-970. doi: 10.1038/onc.2017.367. Epub 2017 Oct 23.
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.
抗糖尿病双胍类药物二甲双胍可能通过代谢调节表观基因组发挥促进健康的作用。在这里，我们表明二甲双胍通过降低 S-腺苷同型半胱氨酸 (SAH) 来促进非癌性、易患癌和转移性癌细胞的全基因组 DNA 甲基化，SAH 是 S-腺苷甲硫氨酸 (SAM)-依赖性 DNA 甲基转移酶的强反馈抑制剂，同时促进 SAM 的积累，SAM 是细胞甲基化的通用甲基供体。通过使用二甲双胍和线粒体/复合物 I (mCI)-靶向二甲双胍类似物 (norMitoMet) 在野生型和 AMP 激活蛋白激酶 (AMPK)-、丝氨酸羟甲基转移酶 2 (SHMT2)-和 mCI-缺失细胞的实验对中，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通量和 CI 活性之间的偶联来增加与 SAM:SAH 比值相关的甲基化能力。通过增加叶酸储存中一碳单位对 SAM 的贡献，同时响应 AMPK 感知的能量危机降低 SAH，二甲双胍可以作为一种代谢 - 表观遗传调节剂，能够重新编程连接细胞代谢和 DNA 甲基化机制的关键途径之一。
