Glucose depletion activates mmu-miR-466h-5p expression through oxidative stress and inhibition of histone deacetylation.
MicroRNAs (miRNAs) are involved in the regulation of multiple cellular processes. Changes of miRNA expression have been linked to the development of various diseases including cancer, but the molecular events leading to these changes at different physiological conditions are not well characterized. Here we examined the intracellular events responsible for the miR-466h-5p activation in mouse cells exposed to glucose deprivation. MiR-466h-5p is a member of the miR-297-669 cluster located in intron 10 of Sfmbt2 gene on mouse chromosome 2 and has a pro-apoptotic role. We showed that the time-dependant activation of miR-466h-5p, miR-669c and the Sfmbt2 gene followed the inhibition of histone deacetylation caused by glucose deprivation-induced oxidative stress. This oxidative stress causes the accumulation of reactive oxygen species (ROS) and depletion of reduced glutathione (GSH) that together inhibited histone deacetylases (HDACs) activity, reduced protein levels of HDAC2 and increased acetylation in miR-466h-5p promoter region, which led to the activation of this miRNA. Based on this study and previous work, we suggest a possible role of miR-466h-5p (and miR 297-669 cluster) in the cells during toxic metabolites accumulation. Improved characterization of the molecular events that lead to the activation of miR-466h-5p may provide a better understanding of the relation between cellular environment and miRNA activation.
Biotechnology Core Laboratory National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health Bldg 14A Bethesda, MD 20892, USA.
Aliaksandr
A
Druz
Michael
M
Betenbaugh
Joseph
J
Shiloach
D000107:Acetylation; D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation; D005947:Glucose / Q000502:physiology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic; D017382:Reactive Oxygen Species / Q000378:metabolism; D012097:Repressor Proteins; D014157:Transcription Factors / Q000235:genetics
D056572:Histone Deacetylase Inhibitors; D006657:Histones; D035683:MicroRNAs; C576133:Mirn466 microRNA, mouse; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; C527638:Sfmbt2 protein, mouse; D014157:Transcription Factors; D006861:Hydrogen Peroxide; D006655:Histone Deacetylases; D005947:Glucose