ArticleScientific reports2019
Metformin activates KDM2A to reduce rRNA transcription and cell proliferation by dual regulation of AMPK activity and intracellular succinate level.
Article in Scientific reports, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 32 citations in OpenAlex.
- Circular RNAs in Diabetic Foot Ulcers: A Scoping Review of Clinical, Preclinical, and In Silico Evidence on Diagnostic and Therapeutic Potentials.Endocrinology, diabetes & metabolism · 2026Article
- TORC2 inactivation promotes heterochromatin formation in rDNA and prolongs viability of quiescent fission yeast cells.Communications biology · 2025Article
- SLC25A11 Is Associated with KDM2A-Dependent Reduction in rRNA Transcription Induced by Aminooxyacetic Acid.Cells · 2025Article
- Autophagy in adult stem cell homeostasis, aging, and disease therapy.Cell regeneration (London, England) · 2025Review
- Review
- Tumor promoting effect of PDLIM2 downregulation involves mitochondrial ROS, oncometabolite accumulations and HIF-1α activation.Journal of experimental & clinical cancer research : CR · 2024Article
- Circ_072697 knockdown promotes advanced glycation end products-induced cell proliferation and migration in HaCaT cells via miR-3150a-3p/KDM2A axis.BMC endocrine disorders · 2023Article
- Microarray analysis of breast cancer gene expression profiling in response to 2-deoxyglucose, metformin, and glucose starvation.Cancer cell international · 2022Article
- Gallic Acid Derivatives Propyl Gallate and Epigallocatechin Gallate Reduce rRNA Transcription via Induction of KDM2A Activation.Biomolecules · 2021Article
- AMPK: restoring metabolic homeostasis over space and time.Molecular cell · 2021Review
- Histone demethylase KDM2A: Biological functions and clinical values (Review).Experimental and therapeutic medicine · 2021Review
- Article
- Metformin: Sentinel of the Epigenetic Landscapes That Underlie Cell Fate and Identity.Biomolecules · 2020Review
- Metformin: Targeting the Metabolo-Epigenetic Link in Cancer Biology.Frontiers in oncology · 2020Review
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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