Unlocking the potential of melatonin: A promising epigenetic weapon against cancer

By Bhavana KunkalikarMay 30 2023Reviewed by Benedette Cuffari, M.Sc.

In a recent study published in the journal Antioxidants, researchers discuss the potential role of melatonin in regulating deoxyribonucleic acid (DNA) methylation.

Study: Melatonin: A Potential Regulator of DNA Methylation. Image Credit: Yuriy Golub / Shutterstock.com

The health effects of melatonin

Melatonin, a hormone produced by the pineal gland, plays a crucial role in regulating various cellular processes such as chronobiology, apoptosis, proliferation, oxidative damage, immune regulation, pigmentation, and mitochondrial metabolism. Previous studies have identified a relationship between disruption of the circadian cycle and genomic instability, including changes in DNA methylation patterns.

The potential role of melatonin in regulating DNA methylation is a promising area of exploration due to the impact of genomic instability on cancer initiation and non-malignant disease development, as DNA methylation has emerged as a novel target in clinical therapy.

The role of melatonin in DNA methylation

Melatonin regulates DNA methyltransferases (DNMTs) expression

Melatonin plays a crucial role in regulating gene expression, including genes related to epigenetic processes, due to its diverse biological effects. Melatonin also affects DNA methylation levels, which can lead to increased cell differentiation.

Melatonin reduces the methylation level (5-mC) by suppressing DNMT1 and methyl CpG binding protein 2 (MeCP2) expression. However, melatonin does not appear to impact on the expression levels of DNMT3A and DNMT3B, which is responsible for de novo methylation. Thus, melatonin may have a stronger effect on preserving DNA methylation during DNA replication. 

The potential impact of melatonin on ten-eleven translocation (TET) proteins

TET proteins are responsible for DNA demethylation, which accounts for a significant portion of the DNA methylation status in the genome. The impact of melatonin on DNMTs expression suggests that this hormone may affect active DNA demethylation.

For example, one study reported that mouse embryos lacking aralkylamine N-acetyltransferase (AANAT), the key enzyme in melatonin production, exhibited reduced TET2 expression and alterations in DNA methylation. Notably, this process was reversible with melatonin supplementation.

Melatonin and DNA methylation under artificial light at night (ALAN)

The production of melatonin is disturbed by exposure to ALAN. Melatonin synthesis in the pineal gland is regulated by retinal ganglion cells that contain melanopsin, a photopigment that is highly sensitive to short-wavelength light. Exposure to ALAN can lead to reduced melatonin secretion.

Previous studies have shown that decreased levels of melatonin caused by ALAN may contribute to higher rates of hormone-dependent cancers. Furthermore, ALAN could be accountable for the growth of tumors and development of global DNA hypomethylation in the 4T1 breast cancer tumors of BALB/c short-day-acclimated mice.

Exposure to ALAN has been attributed to DNA hypomethylation in the pancreatic tissue, as well as lower glucose and insulin levels in rats, thus reflecting the significant impact of ALAN on metabolic responses. One recent study found that exposure to ALAN is linked to higher rates of cardiovascular diseases, diabetes, and obesity, especially among elderly patients.

MT1 melatonin receptor (MTNR)-1B hypermethylation has been proposed as a new epigenetic marker for atherosclerosis, a metabolic disease. Taken together, these studies indicate a strong connection between melatonin function and DNA methylation status.

Melatonin and methylation in cell development and differentiation

In one study on hamster breeding, researchers found that the use of winter-like melatonin led to reduced DNMT expression in the hypothalamus, thereby resulting in the hypomethylation of the dio3 promoter, which led to gonadal regression.

Melatonin also appears to directly impact embryo development through its involvement in the reprogramming of DNA methylation. Melatonin can also enhance the development of embryos by inducing modifications in the DNA methylation of genes associated with pluripotency and tissue-specific functions.

The impact of melatonin on stem cell differentiation has been previously reported. Melatonin promotes odontogenic differentiation of human dental pulp cells (hDPCs) and reduces global DNA methylation and MeCP.

Notably, methylation loss encourages stem cell differentiation, while hypermethylation maintains cell stemness. Moreover, melatonin supplementation induces differentiation in hDPCs through a protein interaction that affects global DNA methylation alterations.

Conclusions

Melatonin has been extensively studied as a potential cancer prevention or treatment option, with a significant and expanding body of literature supporting its efficacy. The current study explored the possible impact of melatonin on DNA methylation.

Melatonin secretion alterations due to night shift work may lead to hypermethylation of genes that are involved in the circadian biorhythm. This suggests that melatonin could potentially have a direct impact on DNA methylation.

Melatonin administration, combined with DNMT inhibitors, may be a valuable addition to anticancer therapy, particularly for tumors exhibiting altered expression of melatonin receptors. Further exploration of this approach is warranted in both experimental and clinical settings.