picture source：https://doi.org/10.1111/jpi.12765

Melatonin (N-acetyl-5-methoxytryptamine) is a naturally occurring indole compound, which is mainly synthesized and secreted by the pineal gland during sleep. Its function in the brain to help maintain the circadian rhythm of physiological processes is well known. Melatonin also exists in other tissues. More and more evidence shows that it has a variety of physiological and pharmacological effects, including anti-inflammatory, anti-tumor, antioxidant and anti-aging. On the basis of its anti proliferation and pro apoptosis effects, melatonin can inhibit the growth of some types of cancer. It can promote apoptosis by regulating the expression of Bcl-2, caspase-3 and caspase-9, inhibit the proliferation of tumor cells through PI3K / Akt pathway, and prevent the secondary growth of cancer cells in the distance by limiting the entry of cancer cells into the vascular system, so as to inhibit the molecular process related to tumor metastasis. In the combined treatment of sorafenib, adriamycin and other anticancer drugs, melatonin shows a strong anticancer effect in vitro and in vivo.

Melatonin plays a key role in regulating glucose homeostasis and energy metabolism. The decrease of melatonin level will lead to the changes of insulin resistance, glucose tolerance and other metabolic parameters, while melatonin supplementation can enhance glucose tolerance by restoring the expression of GLUT4 gene. Glucose is the main monosaccharide in carbohydrate metabolism. It is the main energy of most organisms and can be transformed into all other sugars used for glycosylation.

Glycosylation is a very common post-translational modification. Abnormal glycosylation is closely related to tumor progression and metastasis. O-connected β- N-acetylglucosamine (o-glcn-aegarization) is a protein glycosylation that binds to the hydroxyl groups of serine and / or threonine residues. It is a unique post-translational modification of carbohydrates. Unlike other complex glycosylation, O-GlcNAc on Ser / Thr usually does not extend further. In mammalian cells, β- N-acetylglucosamine transferase and β- N-acetylglucosaminidase is responsible for the addition and removal of GlcNAc, respectively. O-glcnacylated protein is not only particularly abundant in cytoplasm and nucleus, but also exists in most cells. O-glcn acylation has been confirmed in many protein species and shows complex crosstalk with protein phosphorylation. O-glcn acylation is often involved in the regulation and function of biosynthetic and metabolic pathways such as cell proliferation, invasion and metastasis.

Mechanism of melatonin inhibiting tumor growth by reducing o-glcn acylation on Cdk5 (schematic)

picture source：https://doi.org/10.1111/jpi.12765

In order to elucidate the role of O-GlcN acylation in the inhibition of tumor growth by melatonin, the level of O-GlcNAc in bladder cancer tissue was determined and melatonin was used to treat bladder cancer cells. Cell proliferation and migration decreased, and the level of O-GlcNAc decreased. The mechanism of melatonin induced the decrease of O-GlcNAc level in yts-1 cells was discussed. Proteomic and glycoproteomic analysis showed abnormal expression of cyclin dependent kinase like 5 (Cdk5). In vivo and in vitro experiments show that melatonin inhibits the O-GlcNAc modification of Cdk5, and the O-GlcNAc site of t246 plays an important role in Cdk5.

reference：

Jinpeng Wu et al. Melatonin reduces proliferation and promotes apoptosis  of bladder cancer cells by suppressing O- GlcNAcylation of  cyclin- dependent- like kinase 5. J Pineal Res. 2021 Sep 6; e12765. doi: 10.1111/jpi.12765.

（The above pictures and texts are from Bioon.com.）