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: Yuji Tanaka, Hirohisa Yano, Sachiko Ogasawara, Sho-Ichi Yoshioka, Hiromi Imamura, Kengo Okamoto, Makoto Tsuneoka
• Journal: Molecular and cellular biology (Mol Cell Biol) Vol. 35 Issue 24 Pg. 4170-84 (Dec 2015) ISSN: 1098-5549 [Electronic] United States
• PMID: 26416883 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Chemical References

• F-Box Proteins
• Histones
• Pol1 Transcription Initiation Complex Proteins
• RNA, Ribosomal
• RNA, Small Interfering
• RRN3 protein, human
• Deoxyglucose
• Jumonji Domain-Containing Histone Demethylases
• KDM2A protein, human
• PRKAA2 protein, human
• AMP-Activated Protein Kinases
• PRKAA1 protein, human
• Glucose

Topics

• AMP-Activated Protein Kinases (genetics, metabolism)
• Cell Line, Tumor
• Cell Proliferation (genetics)
• DNA Methylation (genetics)
• Deoxyglucose (pharmacology)
• F-Box Proteins (genetics, metabolism)
• Glucose (metabolism)
• Glycolysis (drug effects)
• Histones (metabolism)
• Humans
• Jumonji Domain-Containing Histone Demethylases (genetics, metabolism)
• MCF-7 Cells
• Pol1 Transcription Initiation Complex Proteins (metabolism)
• Promoter Regions, Genetic (genetics)
• RNA Interference
• RNA, Ribosomal (genetics)
• RNA, Small Interfering
• Starvation (metabolism)
• Transcription, Genetic (genetics)
• Triple Negative Breast Neoplasms (metabolism)