title: Mild Glucose Starvation Induces KDM2A-Mediated H3K36me2 Demethylation through AMPK To Reduce rRNA Transcription and Cell Proliferation.
abstract: Environmental conditions control rRNA transcription. Previously, we found that serum and glucose deprivation induces KDM2A-mediated H3K36me2 demethylation in the rRNA gene (rDNA) promoter and reduces rRNA transcription in the human breast cancer cell line MCF-7. However, the molecular mechanism and biological significance are still unclear. In the present study, we found that glucose starvation alone induced the KDM2A-dependent reduction of rRNA transcription. The treatment of cells with 2-deoxy-d-glucose, an inhibitor of glycolysis, reduced rRNA transcription and H3K36me2 in the rDNA promoter, both of which were completely dependent on KDM2A in low concentrations of 2-deoxy-d-glucose, that is, mild starvation conditions. The mild starvation induced these KDM2A activities through AMP-activated kinase (AMPK) but did not affect another AMPK effector of rRNA transcription, TIF-IA. In the triple-negative breast cancer cell line MDA-MB-231, the mild starvation also reduced rRNA transcription in a KDM2A-dependent manner. We detected KDM2A in breast cancer tissues irrespective of their estrogen receptor, progesterone receptor, and HER2 status, including triple-negative cancer tissues. In both MCF-7 and MDA-MB-231 cells, mild starvation reduced cell proliferation, and KDM2A knockdown suppressed the reduction of cell proliferation. These results suggest that under mild glucose starvation AMPK induces KDM2A-dependent reduction of rRNA transcription to control cell proliferation.
authors.affiliation: Laboratory of Molecular and Cellular Biology, Faculty of Pharmacy, Takasaki University of Health and Welfare, Takasaki, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Department of Pathology, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Yano
authors.affiliation: Department of Pathology, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Ogasawara
authors.affiliation: Laboratory of Molecular and Cellular Biology, Faculty of Pharmacy, Takasaki University of Health and Welfare, Takasaki, Japan.
authors.forename: Sho-Ichi
authors.initials: S
authors.lastname: Yoshioka
authors.affiliation: Hakubi Center for Advanced Research, Kyoto University, Kyoto, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Imamura
authors.affiliation: Laboratory of Molecular and Cellular Biology, Faculty of Pharmacy, Takasaki University of Health and Welfare, Takasaki, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Okamoto
authors.affiliation: Laboratory of Molecular and Cellular Biology, Faculty of Pharmacy, Takasaki University of Health and Welfare, Takasaki, Japan tsuneoka@takasaki-u.ac.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Tsuneoka
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D003847:Deoxyglucose / Q000494:pharmacology; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006657:Histones / Q000378:metabolism*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D061986:MCF-7 Cells; D035463:Pol1 Transcription Initiation Complex Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D034622:RNA Interference; D012335:RNA, Ribosomal / Q000235:genetics; D034741:RNA, Small Interfering; D013217:Starvation / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism
chemical_list: D044783:F-Box Proteins; D006657:Histones; D035463:Pol1 Transcription Initiation Complex Proteins; D012335:RNA, Ribosomal; D034741:RNA, Small Interfering; C428423:RRN3 protein, human; D003847:Deoxyglucose; D056484:Jumonji Domain-Containing Histone Demethylases; C534524:KDM2A protein, human; C526181:PRKAA2 protein, human; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human; D005947:Glucose