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

• Published in: Scientific reports Vol. 9; no. 1; pp. 18694 - 12
• Main Authors: Tanaka, Yuji, Konishi, Akimitsu, Obinata, Hideru, Tsuneoka, Makoto
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10-12-2019; Nature Publishing Group
• Subjects: 38; 38/90; 631/337/176; 631/337/572; 96; AMP-Activated Protein Kinases - metabolism; Antidiabetics; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Diabetes Mellitus, Type 2 - genetics; DNA, Ribosomal - genetics; F-Box Proteins - drug effects; F-Box Proteins - genetics; F-Box Proteins - metabolism; Glucose - metabolism; Histones - metabolism; Humanities and Social Sciences; Humans; Hypoglycemic Agents - pharmacology; Jumonji Domain-Containing Histone Demethylases - drug effects; Jumonji Domain-Containing Histone Demethylases - metabolism; Ketoglutaric acid; Kinases; MCF-7 Cells; Metformin; Metformin - metabolism; Metformin - pharmacology; multidisciplinary; Organic acids; Phosphates; Promoter Regions, Genetic - drug effects; RNA, Ribosomal - metabolism; rRNA; Science; Science (multidisciplinary); Succinic Acid - metabolism; Transcription; Transcription, Genetic - drug effects
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-55075-0

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.