Melatonin: Epigenetic mechanisms in cancer inhibition

Heritable changes in gene expression that do not involve alterations in DNA sequences are now known to be involved in diseases. Two important epigenetic changes to contribute to disease are abnormal methylation patterns of DNA and modifications of histone in chromatin. Epimutations, such as the hypermethylation and epigenetic silencing of genes, open new avenues of treatment. Melatonin is mainly secreted by pineal gland during the dark period. Therefore, the blood levels are always higher at night. In addition to its elevated blood levels at night, melatonin synthesis occurs in many cell types independent of the circadian rhythmicity of pineal secretion. This indolamine has multiple membrane receptor-mediated and receptor-independent actions. These functions include the control of seasonal reproduction, modulation of sleep processes and influences on bone growth and osteoporosis. Among the actions of melatonin that are likely receptor independent include its ability to neutralize virtually all oxygen and nitrogen-based reactants. It is well documented that melatonin is more effective than several well-known antioxidants including vitamins A, C, E, and N-acetylcysteine. Melatonin functions in every cell and subcellular compartment since there are no morpho-physiological barriers to melatonin. Although little is known about nuclear actions of melatonin and nuclear melatonin receptors (NMRs), melatonin has a variety functions within the nuclear compartment including inhibition of transcription factors binding to DNA and influences on gene expression or inhibition at the transcriptional level. Moreover, melatonin influences transcriptional activity of several nuclear receptors and co-modulators. Recent evidence has revealed that melatonin affects histone modification and DNA methylation enzymes directly or through nuclear receptors and co-modulators. Therefore, melatonin seems to influence epigenetic processes within cells. The last two decades has witnessed a marked interest in melatonin and it has become a strong candidate to treat several types of cancers. Several epigenetic actions of melatonin, therefore, appear to be involved in the mechanisms of cancer inhibition. In this chapter, actions of melatonin as they directly or indirectly involve epigenetic mechanisms are reviewed with a special focus on cancer.