Genome-wide profiling in melatonin-exposed human breast cancer cell lines identifies differentially methylated genes involved in the anticancer effect of melatonin.
ABSTRACT Epigenetic alterations have emerged as an important mechanism involved in tumorigenesis. The epigenetic impact of DNA methylation in various types of human cancer is not completely understood. Previously, we observed melatonin-induced differential expression of miRNA and miRNA-related genes in human breast cancer cell lines that indicated an anticancer effect of melatonin. In this report, we further characterized epigenetic changes in melatonin-exposed MCF-7 cells through the analysis of DNA methylation profiles in breast cancer cells to provide new insights into the potential mechanisms of the anticancer effect of melatonin. Microarray-based DNA methylation and gene expression profiling were carried out using human breast cancer cell lines. We further identified a number of mRNAs whose expression levels show an inverse correlation with DNA methylation levels. The mRNA expression levels and methylation status of candidate genes in melatonin-exposed cells were confirmed by real-time quantitative PCR and bisulfite PCR. This approach led to the detection of cancer-related genes, which were oncogenic genes, including EGR3 and POU4F2/Brn-3b were down-regulated, while the tumor suppressor gene, GPC3, was up-regulated by 1 nm melatonin-treated MCF-7 cells. Our results provide detailed insights into the DNA methylation patterns induced by melatonin and suggest a potential mechanism of the anticancer effect of aberrant DNA methylation in melatonin-treated breast cancer cells.
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ABSTRACT: MicroRNAs (miRNAs) are a class of small noncoding RNAs, producing transcripts of about 22 nucleotides in length. miRNAs usually function as antisense regulators of other RNAs by degrading their targets. Recently, miRNAs have emerged as interesting new drug targets due to their regulatory role in essential biological processes. Salvianolic acid B (SalB) is one of the major pharmacologically active ingredients of Salvia miltiorrhiza, a traditional oriental medicine for treatment of cardiovascular disorders. In this study, we determined whether miRNAs play a role in regulation of various gene expression responses to SalB in human umbilical vein endothelial cells (HUVECs). We used the microarray approach to evaluate levels of both miRNA and mRNA, and found that 171 miRNAs were differentially expressed in SalB-treated HUVECs. We additionally identified 848 messenger RNAs (mRNAs) that are anti-correlated with the miRNAs expression. The Gene Ontology (GO) term enrichment was analyzed for identification of biological processes of target genes affected by differential expression of miRNA. Among 848 genes investigated, cardiovascular diseaserelated genes were selected in SalB-treated HUVECs. These results suggest that SalB may modulate miRNA and their target gene expression in order to exert vascular protective effects in human endothelial cells.Molecular and Cellular Toxicology 9(1). · 0.72 Impact Factor
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ABSTRACT: Brain aging is linked to certain types of neurodegenerative diseases and identifying new therapeutic targets has become critical. Melatonin, a pineal hormone, associates with molecules and signaling pathways that sense and influence energy metabolism, autophagy, and circadian rhythms, including insulin-like growth factor 1 (IGF-1), Forkhead box O (FoxOs), sirtuins and mammalian target of rapamycin (mTOR) signaling pathways. This review summarizes the current understanding of how melatonin, together with molecular, cellular and systemic energy metabolisms, regulates epigenetic processes in the neurons. This information will lead to a greater understanding of molecular epigenetic aging of the brain and anti-aging mechanisms to increase lifespan under healthy conditions.International Journal of Molecular Sciences 01/2014; 15(9):16848-16884. · 2.46 Impact Factor
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ABSTRACT: Melatonin is a highly pleiotropic regulator molecule, which influences numerous functions in almost every organ and, thus, up- or down-regulates many genes, frequently in a circadian manner. Our understanding of the mechanisms controlling gene expression is actually now expanding to a previously unforeseen extent. In addition to classic actions of transcription factors, gene expression is induced, suppressed or modulated by a number of RNAs and proteins, such as miRNAs, lncRNAs, piRNAs, antisense transcripts, deadenylases, DNA methyltransferases, histone methylation complexes, histone demethylases, histone acetyltransferases and histone deacetylases. Direct or indirect evidence for involvement of melatonin in this network of players has originated in different fields, including studies on central and peripheral circadian oscillators, shift work, cancer, inflammation, oxidative stress, aging, energy expenditure/obesity, diabetes type 2, neuropsychiatric disorders, and neurogenesis. Some of the novel modulators have also been shown to participate in the control of melatonin biosynthesis and melatonin receptor expression. Future work will need to augment the body of evidence on direct epigenetic actions of melatonin and to systematically investigate its role within the network of oscillating epigenetic factors. Moreover, it will be necessary to discriminate between effects observed under conditions of well-operating and deregulated circadian clocks, and to explore the possibilities of correcting epigenetic malprogramming by melatonin.International Journal of Molecular Sciences 01/2014; 15(10):18221-18252. · 2.46 Impact Factor