MicroRNA-539 Is Up-regulated in Failing Heart, and Suppresses O-GlcNAcase Expression

Background: Protein O-GlcNAcylation is nearly ubiquitous; however, regulation of the expression of key enzymes remains unknown. Results: miR-539 is up-regulated in the failing heart, binds to the 3UTR, and negatively regulates O-GlcNAcase expression. Conclusion: Protein O-GlcNAcylation can be regulated by post-transcriptional mechanisms. Significance: miR-539 regulates one of the two enzymes responsible for O-GlcNAcylation in multicellular eukaryotes. Derangements in metabolism and related signaling pathways characterize the failing heart. One such signal, O-linked -N-acetylglucosamine (O-GlcNAc), is an essential post-translational modification regulated by two enzymes, O-GlcNAc transferase and O-GlcNAcase (OGA), which modulate the function of many nuclear and cytoplasmic proteins. We recently reported reduced OGA expression in the failing heart, which is consistent with the pro-adaptive role of increased O-GlcNAcylation during heart failure; however, molecular mechanisms regulating these enzymes during heart failure remain unknown. Using miRNA microarray analysis, we observed acute and chronic changes in expression of several miRNAs. Here, we focused on miR-539 because it was predicted to target OGA mRNA. Indeed, co-transfection of the OGA-3UTR containing reporter plasmid and miR-539 overexpression plasmid significantly reduced reporter activity. Overexpression of miR-539 in neonatal rat cardiomyocytes significantly suppressed OGA expression and consequently increased O-GlcNAcylation; conversely, the miR-539 inhibitor rescued OGA protein expression and restored O-GlcNAcylation. In conclusion, this work identifies the first target of miR-539 in the heart and the first miRNA that regulates OGA. Manipulation of miR-539 may represent a novel therapeutic target in the treatment of heart failure and other metabolic diseases.