二甲双胍通过双重调节AMPK活性和细胞内琥珀酸水平来激活KDM2A以减少rRNA转录和细胞增殖。,Scientific Reports

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二甲双胍通过双重调节AMPK活性和细胞内琥珀酸水平来激活KDM2A以减少rRNA转录和细胞增殖。
Scientific Reports ( IF 3.8 ) Pub Date : 2019-12-10 , DOI: 10.1038/s41598-019-55075-0
Yuji Tanaka ₁ , Akimitsu Konishi ₂ , Hideru Obinata ₃ , Makoto Tsuneoka ₁

Affiliation

二甲双胍用于治疗2型糖尿病。二甲双胍激活AMP激活的激酶（AMPK），这可能有助于二甲双胍的作用。二甲双胍也显示出抗增殖活性。但是，该机制仍然未知。我们发现用二甲双胍处理MCF-7细胞可诱导rDNA启动子中KDM2A的脱甲基酶活性，从而降低rRNA转录和细胞增殖。AMPK活性是二甲双胍激活KDM2A所必需的。由于JmjC型酶的脱甲基酶活性需要将α-酮戊二酸转化为琥珀酸酯的副反应，因此这些有机酸可能会影响其脱甲基酶活性。我们发现二甲双胍在α-酮戊二酸水平降低的条件下不会诱导KDM2A脱甲基酶活性。二甲双胍经过四个小时的治疗后，琥珀酸含量降低了，琥珀酸的补给抑制了二甲双胍对KDM2A的激活，但不抑制AMPK的激活。即使在抑制AMPK活性的条件下，二甲双胍也会还原琥珀酸。这些结果表明二甲双胍激活AMPK并降低细胞内琥珀酸水平，这两者都是激活KDM2A减少rRNA转录所必需的。本文介绍的结果揭示了二甲双胍作用的新因素，即细胞内琥珀酸的减少，这有助于二甲双胍的抗增殖活性。这些结果表明二甲双胍激活AMPK并降低细胞内琥珀酸水平，这两者都是激活KDM2A减少rRNA转录所必需的。本文介绍的结果揭示了二甲双胍作用的新因素，即细胞内琥珀酸的减少，这有助于二甲双胍的抗增殖活性。这些结果表明二甲双胍激活AMPK并降低细胞内琥珀酸水平，这两者都是激活KDM2A减少rRNA转录所必需的。本文介绍的结果揭示了二甲双胍作用的新因素，即细胞内琥珀酸的减少，这有助于二甲双胍的抗增殖活性。

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Metformin activates KDM2A to reduce rRNA transcription and cell proliferation by dual regulation of AMPK activity and intracellular succinate level.

Metformin is used to treat type 2 diabetes. Metformin activates AMP-activated kinase (AMPK), which may contribute to the action of metformin. Metformin also shows anti-proliferation activity. However, the mechanism is remained unknown. We found that treatment of MCF-7 cells with metformin induced the demethylase activity of KDM2A in the rDNA promoter, which resulted in reductions of rRNA transcription and cell proliferation. AMPK activity was required for activation of KDM2A by metformin. Because demethylase activities of JmjC-type enzymes require a side reaction converting α-ketoglutarate to succinate, these organic acids may affect their demethylase activities. We found that metformin did not induce KDM2A demethylase activity in conditions of a reduced level of α-ketoglutarate. A four-hour treatment of metformin specifically reduced succinate, and the replenishment of succinate inhibited the activation of KDM2A by metformin, but did not inhibit the activation of AMPK. Metformin reduced succinate even in the conditions suppressing AMPK activity. These results indicate that metformin activates AMPK and reduces the intracellular succinate level, both of which are required for the activation of KDM2A to reduce rRNA transcription. The results presented here uncover a novel factor of metformin actions, reduction of the intracellular succinate, which contributes to the anti-proliferation activity of metformin.

更新日期：2019-12-11

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