Your privacy, your choice

We use essential cookies to make sure the site can function. We also use optional cookies for advertising, personalisation of content, usage analysis, and social media.

By accepting optional cookies, you consent to the processing of your personal data - including transfers to third parties. Some third parties are outside of the European Economic Area, with varying standards of data protection.

See our privacy policy for more information on the use of your personal data.

for further information and to change your choices.

Skip to main content
  • Review Letter
  • Open access
  • Published:

Melatonin and cancer suppression: insights into its effects on DNA methylation

Abstract

Melatonin is an important naturally occurring hormone in mammals. Melatonin-mediated biological effects include the regulation of circadian rhythms, which is important for optimal human health. Also, melatonin has a broad range of immunoenhancing actions. Moreover, its oncostatic properties, especially regarding breast cancer, involve a variety cancer-inhibitory processes and are well documented. Due to their promising effects on the prognosis of cancer patients, anti-cancer drugs with epigenetic actions have attracted a significant amount of attention in recent years. Epigenetic modifications of cancers are categorized into three major processes including non-coding RNAs, histone modification, and DNA methylation. Hence, the modification of the latter epigenetic event is currently considered an effective strategy for treatment of cancer patients. Thereby, this report summarizes the available evidence that investigated melatonin-induced effects in altering the status of DNA methylation in different cancer cells and models, e.g., malignant glioma and breast carcinoma. Also, we discuss the role of artificial light at night (ALAN)-mediated inhibitory effects on melatonin secretion and subsequent impact on global DNA methylation of cancer cells.

Melatonin and its role in human health

Melatonin is an endogenous metabolic hormone that has an obvious association with the regulation of circadian rhythms. In addition to its effect in sleep promotion, melatonin has many other functions including its role in neutralizing reactive oxygen species (ROSs), identified as its antioxidant properties, immunomodulation and inflammatory disorders, and anti-viral actions [1,2,3]. Moreover, the evidence is compelling that melatonin has a variety of anti-cancer effects, such as its inhibition of cancer cell viability, proliferation, progression, and metastasis or even inhibition of cancer initiation [3, 4]. This has drawn attention to the potential use of melatonin for cancer treatment in the clinical setting, although huge obstacles still exist before its wide clinical administration is accepted [5].

Melatonin biosynthesis

Melatonin (N-acetyl-5-methoxy-tryptamine) is an endogenous hormone was discovered in bovine pineal tissue of bovine by Lerner and colleagues in 1958 [6]. Later, melatonin was reported to be existed in different plants, unicellular organisms such as bacteria, and clades of invertebrates [7,8,9]. The pineal gland releases melatonin into the third ventricle and into the blood. Furthermore, the biosynthesis of melatonin occurs in bone marrow and lymphocytes, gastrointestinal (GI) tract, and eyes, etc., and perhaps in every cell [10]. Melatonin biosynthesis take places in the mitochondria of eukaryotic cells [11]. Initially, cells take up the essential circulating amino acid, tryptophan, and then convert it to 5-hydroxytryptophan, and serotonin in two consecutive reactions catalyzed by tryptophan hydroxylase, and 5-hydroxytryptophan decarboxylase, respectively. After a reaction catalyzed by aralkylamine N-acetyltransferase (AANAT), serotonin transformed into N-acetyl-5-hydroxytryptamine, succeed by its methylation to melatonin by acetylserotonin-O-methyltransferase [12].

The “master biological clock”, located in the suprachiasmatic nucleus (SCN) of the hypothalamus, has essential regulatory actions in determining the rhythmic production of pineal melatonin; this master circadian regulator is present in the brain of all mammals including the human [13]. Photoreceptor cells of retina respond to light information with the neural signal being transferred to the hypothalamic SCN through the retinohypothalamic tract located in the optic nerve. The SCN by means of efferent neurons sends this information via intermediolateral column to superior cervical ganglia (SCG), with the postganglionic sympathetic fibers then projecting to the pineal gland to suppress melatonin synthesis. In the absence of light at night, sympathetic neurons ending in the pineal release noradrenaline which leads to the AANAT activation, and subsequently increases the production and release of melatonin. After its release into the CSF and blood, melatonin exerts a plethora of biological effects as enumerated above.

Melatonin has an extended range of biological activities

Melatonin possesses a wide spectrum of biological and physiological properties, including its effects on the regulation of circadian rhythms and its remarkable efficacy as an anti-oxidant [1]. In addition, studies have shown that the melatonin and immune system have a two-way association: the immune system has actions that promote melatonin biosynthesis and, conversely, melatonin modulates immune system responsivity [14]. Interestingly, melatonin also has potent anti-inflammatory properties via reducing the expression levels of tumor necrosis factor alpha (TNF-α), interferon-gamma (IFN-γ), and interleukin-2 (IL-2) and by up-regulating the expression of anti-inflammatory cytokines such as, IL-4, IL-10, and IL-27 [15]. A large number of investigations have reported promising melatonin-induced regulatory impacts on cancer management in numerous stages of this chronic disorder, such as cancer initiation, progression, and metastasis [16]. Accordingly, affecting distinct metastatic-related molecular pathways and cellular processes including matrix metalloproteinases (MMPs), Rho-associated kinase protein‐1, and epithelial-to-mesenchymal transition (EMT), melatonin has promising properties against metastasis of tumoral cells [17, 18].

These biological properties have a broad spectrum of molecular mechanisms, including binding to receptors of cell membranes, interacting with different proteins in cytosol and nucleus, and direct scavenging of free radicals such as ROSs [1]. Three different classes of putative receptors for melatonin have been characterized: in the membrane, MT1 and MT2 are members of the superfamily of G-protein-coupled receptors which are encoded by MTNR1A and MTNR1B, respectively, [19]; retinoid orphan receptors (RORs), located in the nucleus, belong to the steroid receptor superfamily; they have been shown to bind melatonin [20, 21]; finally, the MT3 melatonin binding site, also is known as quinone reductase 2 (QR2), is situated in the cytosol [22]. Melatonin-induced activation of either MT1 or MT2 receptors causes decreased activity of adenylyl cyclase and, subsequently, reduced levels of cyclic adenosine monophosphate (cAMP); this leads to protein kinase A (PKA) activity repression. Additionally, MT2 also interferes with the activation of guanylyl cyclase and the subsequent formation of cyclic guanosine monophosphate (cGMP) [23]. MT3 functions in detoxification and as an anti-oxidant enzyme and in the reduction of cell proliferation [24]. The membrane receptors for melatonin occur in the majority of cell types such as pituitary gland, brain, hypothalamic SCN, retinal, renal, pancreatic, fat, and immune cells [25, 26].

Melatonin’s widely different biological actions involve the induction distinct mechanisms. The precise melatonin application in numerous diseases and health problems could be facilitated by a thorough understanding of the identified mechanisms [27]. Melatonin structural modification based upon its different receptors, could be considered as an effective strategy for decreasing the specific melatonin-mediated effects.

Epigenetic regulatory mechanisms

Histone modifications, non-coding RNAs, and DNA methylation are major epigenetic processes for altering transcription without inducing any changes in DNA sequence of mammalian cells. These processes are potent biological regulators of various cellular activities and are influenced by environmental agents including nutrition status, stress and infections, chemical substances and drugs [28, 29]. Studies have shown that alterations in epigenetic status are strongly associated with the incidence of neoplasms [30, 31], autoimmune diseases [32], obesity and cardiovascular diseases (CVDs) [33], and type 2 diabetes mellitus (T2DM) [34]. Therefore, identifying novel bioactive chemicals for modification of epigenetic processes, especially in patients with cancer, is considered an effective approach for establishing novel treatments for these patients. In this review, we discuss how melatonin affects epigenetic modifications with a special focus on its ability to influence DNA methylation.

DNA methylation

DNA methylation dynamics are considered promising epigenetic signatures and many studies have extensively investigated in comparison with other epigenetic processes. In recent years, dynamic control of DNA methylation has been widely incorporated into modern epigenetic models. In mammals, DNA epigenetic modifications generally involve a methyl group (-CH3) addition to a cytosine nucleotide, with the subsequent generation of 5-methylcytosine (5mC). Controlling the DNA methylation is the principal function of a family of enzymes named DNA methyltransferases (DNMTs) [35]. In mammals, methylation of DNA frequently occurs in the CpG dinucleotide islands. CpG dinucleotide framework is presented as cytosine and guanine and a phosphate group between these two nucleotides. CpG islands are recognized as dense CpG dinucleotides frequently occurring in promoter and other regulatory regions such as in interspersed areas [36,37,38,39]. The number of CpG sites in the human genome is estimated to be about 29 million. Approximately 60–80% of these sites are methylated in human somatic cells [40]. It is clear that CpG sites do not have a uniform distribution pattern in the genome; conversely, a greater part of the genome is devoid of CpG sites [36, 41, 42]. Interestingly, methylation of DNA take places in 70% and 40% of all CpG dinucleotides, and CpG-rich island genes, respectively [43]. Different methyl-binding proteins recognize methylated CpG dinucleotides as binding sites participating in the recruitment of either protein or machinery of chromatin-remodeling, resulting in the facilitation of gene inactivation and silencing, and condensation of chromatin [44,45,46]. Methylation of DNA in non-CpG sites has also not been found to influence the structure or stability of chromatin, DNA and protein interactions, or gene regulation [47,48,49,50,51].

Aberrant methylation of DNA has been extensively reported to be involved in an extended range of cancer types, including hepatocellular carcinoma (HCC) [52], colorectal cancer (CRC) [53], Wilms tumor [54], breast carcinoma [55], ovarian [56], and bone-related cancers such as osteosarcoma [57]. Besides, emerging evidence evaluating omics technologies have demonstrated that extensive cancer-related differential exists in the methylation of DNA [58,59,60]. As well as, different mutations in DNMTs, differences in DNMTs expression levels, and dysregulated expression of ten-eleven translocation enzymes (TETs) are repeatedly reported in numerous cancer types, they all suggesting a substantial association between aberrant methylation of DNA and cancer incidence [61,62,63,64]. Many studies reported that epigenetic alterations over large chromatin regions in cancer diseases results in epigenetic instability, and subsequent gene expression alterations [65,66,67,68,69]. While epigenetic processes are crucial events for regulating cellular plasticity and stem cell reprogramming in the development of normal cells [70, 71], but disrupted epigenetic alterations such as aberrant DNA methylation in cancer cells can lead to heterogeneity of tumor cells, and subsequent poor prognosis in cancer patients [72,73,74].

Melatonin influences DNA methylation in cancer cells

Glioblastoma is the most prevalent primary tumor of brain. Furthermore, glioblastoma is a highly aggressive and lethal type of cancer; the average of life expectancy is reported to be less than 1 year after it is diagnosed. Because of the difficulty with complete surgical resection and high resistance of glioblastoma to existing chemotherapy agents, treatment of these patients remains exceedingly complicated. Therefore, there is an urgent need for developing unconventional therapeutic strategies in the treatment of patients with malignant glioblastoma. In the past few years, different investigations have shown the existence of stem cell-like cells in solid tumors involving malignant glioblastomas [75]. Stem cell-like cells are important built-in multidrug-resistant and pluripotent cells that commonly develop drug resistance and continue to proliferative after a chemotherapy regimen. Accordingly, the therapeutic approaches that cannot eradicate the brain tumor stem cells (BTSCs) are expected to be unsuccessful. While these treatments may be successful for killing an appreciable number of tumor cells and causing a transitory regression, they fail to alter cancer relapse [76]. For the purpose of achieving a persistent long-lasting treatment of glioblastoma patients, it is a requirement to discover and develop novel therapeutic strategies for targeting both BTSCs and tumor bulk.

Martin and colleagues [77] investigated the properties of melatonin and its combination with chemotherapeutic agents on these multi-drug resistant brain tumor stem cells. Results showed that melatonin and chemotherapeutic drugs in combination induced a remarkable synergistic toxicity against BTSCs and malignant A172 glioma cells. Co-treatment with temozolomide as current agent for remission of malignant glioma with melatonin, significantly correlated with down-regulated expression of ABCG2/BCRP and subsequent inhibition of ABC transporter functions. In fact, melatonin significantly elevated DNA methylation of the promoter of ABCG2/BCRP; thus, the expression properties and function of ABCG2/BCRP were prohibited due to the preincubation melatonin with a DNA methyltransferase inhibitor (DNMTi). Hence, their findings highlight a potent association between the decrease of ABCG2/BCRP activities and the synergistic toxicity of melatonin and therapeutic agents. By inducing DNA methylation in proto-oncogenes, melatonin also could be considered as a promising chemical for defeating multi-drug resistance in malignant glioblastomas, and improving the effectiveness of current chemotherapeutic regimens.

The circadian production and release of melatonin is involved in the regulating periodic events [78]. A photoperiod-independent production of melatonin also typically occurs in the gut. Yet, the physiological roles of locally-produced melatonin in the GI tract is poorly understood. Mannino et al. [79] assessed the melatonin-mediated anti-inflammatory activities in an in vitro model of intestinal inflammation using IL‐1β‐stimulated inflamed intestinal epithelium in Caco‐2 colon cancer cells. Caco‐2 cells differentiated monolayers were preincubated with 1 nmol/L to 50 µmol/L melatonin and then treated with IL‐1β. Following treatment, DNA‐breakage, the status of global DNA methylation, and numerous inflammatory mediators, were assayed. For evaluating the role of membrane receptors of melatonin, they also co-treated differentiated monolayers with melatonin and luzindole, an antagonist of the MT1 and MT2 receptor. The results proved that melatonin at similar concentrations to those absorbed by the intestinal lumen following ingestion of dietary supplements taken for the sleep disorders, decreases the IL‐1β-mediated inflammatory responses. Anti‐inflammatory properties attenuated the levels of pro-inflammatory agents including IL‐6, IL‐8, cyclooxygenase-2 (COX‐2), nitric oxide (NO), and paracellular permeability. Moreover, melatonin-induced protection was also related to decreased activation of nuclear factor-κB (NF‐κB) and prevention of DNA demethylation. In summary, their findings revealed that melatonin, via affecting local physiological activities and DNA methylation, modulates inflammation in the GI tract suggesting a novel therapeutic opportunity for the management of GI-tract-associated chronic disorders such as inflammatory bowel disease (IBD) and also cancer.

In recent decades, the incidence of breast cancer has steadily increased worldwide; also, its incidence is greater in more highly developed countries [80]. Industrialization- and urbanization-associated environmental factors are believed to be potent agents in the etiology of breast cancer. Prolonged and repeated exposure to the artificial light-at-night (ALAN) at night is one of the most prevalent changes of modern life [81]. Emerging evidence has documented a consistent association between ALAN and breast cancer incidence. As an illustration, large epidemiological investigations suggest that extended periods of rotating night shifts in women is associated with a moderate increase in breast cancer risk [82]. Schwimmer et al.[83] hypothesized that ALAN exposure decreases the secretion of melatonin, resulting in the induction of epigenetic modifications and greater growth-rate in breast cancer tumors. They also specifically investigated the impact of exposure to ALAN and exogenous melatonin on the growth-rate of breast cancer tumors. Accordingly, induction of breast cancer in BALB/c short day-acclimated 4T1 breast cancer tumor-bearing mice resulted in greater tumor growth. Results also showed that ALAN-induced impact for increasing growth-rate of breast tumors was strongly reversed by melatonin supplementation and the reduction in tumor growth was accompanied by an induction of global DNA methylation.

In a similar study, via analyzing DNA methylation profiles, Lee and colleagues [84] further investigated melatonin-induced epigenetic alterations in MCF-7 breast cancer cells to achieve a new perspective into the potential mechanisms of melatonin-mediated anti-cancer properties. The candidate genes-associated methylation status and expression levels of mRNAs were confirmed by bisulfite PCR and real-time quantitative PCR (qPCR) in melatonin-exposed cells. This approach using 1 nM melatonin-treated MCF-7 breast cancer cells resulted in the detection of different cancer-related genes, including down-regulated EGR3 and POU4F2/Brn-3b oncogenic genes, and up-regulated GPC3 tumor suppressor gene (TSG). Their findings provided further insights into the melatonin-induced patterns of DNA methylation, and moreover suggest a potential mechanism of the melatonin-mediated anti-cancer properties for modification of aberrant DNA methylation in breast cancer cells.

Agbaria et al.[85] evaluated the impact of 1 × 30 min/midnight ALAN exposure either with or without nocturnal melatonin supplementation on epigenetic processes and inhibition of tumor development in 4T1-inoculated BALB/c mice. At the conclusion of the experiment, the tissues from lungs, liver, spleen and tumor were extracted to analyze the levels of DNMT total activity and global DNA methylation. ALAN-exposed mice showed significant reduction in the levels of 6-sulfatoxymelatonin and remarkable increase in tumor volume, body weight, and lung metastasis in comparison with controls in which all indices were diminished following melatonin supplementation. Compared to tissues from control animals, enzymatic activity and global DNA methylation levels were reported to be lower in breast tumor and liver tissues and higher in lungs and spleen following exposure to ALAN. Their finding proved that ALAN exposure results in the disruption of the melatonin rhythm, which leads to an increased breast cancer burden through influencing the activity of DNMT and global DNA methylation levels. These findings may have utility to be used for early detection and breast cancer management by monitoring melatonin levels and global DNA methylation.

Melatonin-induced inhibition of the chemoresistance of human breast cancer involves different mechanisms including tumor metabolism suppression, inhibition of different kinase enzymes, and transcription factors which usually are activated and involved in drug-resistant breast carcinoma [86]. Various studies have suggested that overexpressed levels of signal transducer and activator of transcription 3 (STAT3) is associated with chemoresistance to paclitaxel in breast cancer patients [87, 88]. Accordingly, STAT3 triggers DNMT1 expression for inducing epigenetic suppression of the transcription of Aplasia Ras homolog one (ARHI), which functions as a tumor suppressor and cytoplasmic STAT3 inhibitor for reversing paclitaxel resistance [89]. Xiang and colleagues [90] demonstrated that exposure of breast tumor–bearing rats to dim light at night (dLAN), and the consequential disrupted expression of the circadian melatonin rhythm resulted in the elevation of phosphorylated and acetylated STAT3 levels, up-regulated DNMT1, and down-regulated expression of ARHI and sirtuin 1 (SIRT1). Additionally, administration of either melatonin or its combination with SIRT1 significantly reversed IL-6-mediated STAT3 acetylation and ARH1 methylation for up-regulating mRNA expression level of ARH1 in MCF-7 cells. The results of this study demonstrated that dLAN-induced disruption of circadian melatonin cycle resulted in chemoresistance to paclitaxel through promoting the expression of STAT3, and melatonin administration remarkably reversed the breast cancer resistance to paclitaxel [91].

Due to the increased use of shorter wavelength illumination because of the advantages it provides, e.g., its energy-efficient properties, these lights have been reported to be associated with a variety of health problems, especially the progression of breast cancer [92]. Zubidat et al.[93] measured the urinary metabolite of melatonin (6-sulfatoxymelatonin), along with monitoring tumor growth and metastases, the status of global DNA methylation, and urinary levels of corticosterone in 4T1 breast cancer cells-tumor bearing female BALB/c mice; they observed ALAN-induced melatonin suppression by four different spectral light compositions (500–595 nm). The findings showed an inverted dose-dependent association between ALAN wavelength and suppression of melatonin. Short wavelength significantly caused an increase in tumor growth, the development of lung metastases, and extended hypomethylation of DNA, although long wavelength light has been reported to be responsible for lessening the mentioned effects. Also, melatonin administration caused a significant reduction of cancer burden. Their results suggested that through inducing aberrant methylation of DNA mediated by melatonin suppression, short wavelength light increases breast cancer burden. Moreover, global DNA methylation and suppression of melatonin secretion are suggested as promising early diagnosis and therapy biomarkers in breast cancer patients [93].

Conclusion

Currently, the utility of melatonin as an anti-cancer agent seems to be a promising and effective strategy for cancer management. One of the newest fields related to its anti-cancer properties is highlighted by its role in the regulation of numerous epigenetic processes including histone modifications, biogenesis of ncRNAs, and modification of DNA methylation. This summary reviewed the studies which investigated the properties of melatonin in the regulation of DNA methylation (Table 1 and Fig. 1). Indeed, we observed that through regulating the expression levels of distinct enzymes such as DNMTs, melatonin significantly modified the status of DNA methylation, especially in breast cancer tissue. Consequently, the changes in DNA methylation led to an inhibition of cancer cell proliferation, progression and metastasis, and reversed chemoresistance to current drug regimens by affecting several molecular pathways. Nevertheless, further well-designed mechanistic investigations are needed for a complete understanding of the molecular implications of melatonin-induced modification of DNA methylation against different cancer types, and the application of this promising agent as part of the chemotherapeutic regimen for patients in clinical practice.

Table 1 Studies that investigated the melatonin-induced modification of DNA methylation against cancer
Fig. 1
figure 1

Melatonin and cancer suppression: Insights into its effects on DNA methylation

Data Availability

Not applicable.

Abbreviations

ROSs:

Reactive oxygen species

GI:

Gastrointestinal

AANAT:

Aralkylamine N-acetyltransferase

SCN:

Suprachiasmatic nucleus

SCG:

Superior Cervical Ganglia

CSF:

Cerebrospinal Fluid

TNF-α:

Tumor Necrosis Factor Alpha

IFN-γ:

Interferon-gamma

IL-2:

Interleukin-2

IL-4:

Interleukin-4

IL-10:

Interleukin-10

IL-27:

Interleukin-27

MMPs:

Matrix metalloproteinases

EMT:

Epithelial-to-mesenchymal transition

QR2:

Quinone reductase 2

cAMP:

Cyclic adenosine monophosphate

PKA:

Protein kinase A

cGMP:

Cyclic guanosine monophosphate

CVDs:

Cardiovascular diseases

T2DM:

Type 2 diabetes mellitus

DNMTs:

DNA methyltransferases

CRC:

Colorectal cancer

TETs:

Ten-eleven translocation enzymes

BTSCs:

Brain Tumor Stem cells

DNMTi:

DNA methyltransferase inhibitor

IL-6:

Interleukin-6

IL‐8:

Interleukin-8

COX‐2:

Cyclooxygenase-2

NO:

Nitric Oxide

NF‐κB:

Nuclear Factor-κB

ALAN:

Artificial Light at Night

IBD:

Inflammatory Bowel Disease

qPCR:

Real-time quantitative PCR

STAT3:

Signal Transducer and Activator of Transcription 3

ARHI:

Aplasia Ras Homolog one

dLAN:

dim Light at Night

SIRT1:

Sirtuin 1

References

  1. Reiter RJ, Ma Q, Sharma R. Melatonin in Mitochondria: Mitigating Clear and Present Dangers. Physiol (Bethesda Md). 2020;35:86–95.

    CAS  Google Scholar 

  2. Hardeland R. COVID-19: Urgent Need to Redesign Anti-inflammatory Strategies for CNS Protection. Central nervous system agents in medicinal chemistry. 2022.

  3. Favero G, Moretti E, Bonomini F, Reiter RJ, Rodella LF, Rezzani R. Promising antineoplastic actions of melatonin. Front Pharmacol. 2018;9:1086.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Monayo SM, Liu X. The prospective application of melatonin in treating epigenetic dysfunctional diseases. Frontiers in Pharmacology. 2022:1593.

  5. Korkmaz A, Reiter RJ. Epigenetic regulation: a new research area for melatonin? J Pineal Res. 2008;44:41–4.

    CAS  PubMed  Google Scholar 

  6. Lerner AB, Case JD, Takahashi Y, Lee TH, Mori W. Isolation of melatonin, the pineal gland factor that lightens melanocyteS1. J Am Chem Soc. 1958;80:2587-.

    Article  CAS  Google Scholar 

  7. Tan D-X, Zheng X, Kong J, Manchester LC, Hardeland R, Kim SJ, et al. Fundamental issues related to the origin of melatonin and melatonin isomers during evolution: relation to their biological functions. Int J Mol Sci. 2014;15:15858–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Paredes SD, Korkmaz A, Manchester LC, Tan D-X, Reiter RJ. Phytomelatonin: a review. J Exp Bot. 2009;60:57–69.

    Article  CAS  PubMed  Google Scholar 

  9. Reiter RJ, Tan D-x, Manchester LC, Simopoulos AP, Maldonado MD, Flores LJ, et al. Melatonin in edible plants (phytomelatonin): identification, concentrations, bioavailability and proposed functions. World Rev Nutr Diet. 2007;97:211–30.

    CAS  PubMed  Google Scholar 

  10. Manchester LC, Coto-Montes A, Boga JA, Andersen LPH, Zhou Z, Galano A, et al. Melatonin: an ancient molecule that makes oxygen metabolically tolerable. J Pineal Res. 2015;59:403–19.

    Article  CAS  PubMed  Google Scholar 

  11. Suofu Y, Li W, Jean-Alphonse FG, Jia J, Khattar NK, Li J, et al. Dual role of mitochondria in producing melatonin and driving GPCR signaling to block cytochrome c release. Proceedings of the National Academy of Sciences. 2017;114:E7997-E8006.

  12. Zhao D, Yu Y, Shen Y, Liu Q, Zhao Z, Sharma R, et al. Melatonin synthesis and function: evolutionary history in animals and plants. Front Endocrinol. 2019;10:249.

    Article  Google Scholar 

  13. Zisapel N. New perspectives on the role of melatonin in human sleep, circadian rhythms and their regulation. Br J Pharmacol. 2018;175:3190–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Skwarlo-Sonta K, Majewski P, Markowska M, Oblap R, Olszanska B. Bidirectional communication between the pineal gland and the immune system. Can J Physiol Pharmacol. 2003;81:342–9.

    Article  CAS  PubMed  Google Scholar 

  15. Hardeland R. Aging, melatonin, and the pro-and anti-inflammatory networks. Int J Mol Sci. 2019;20:1223.

    Article  CAS  PubMed Central  Google Scholar 

  16. Talib WH, Alsayed AR, Abuawad A, Daoud S, Mahmod AI. Melatonin in cancer treatment: Current knowledge and future opportunities. Molecules. 2021;26:2506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Mao L, Summers W, Xiang S, Yuan L, Dauchy RT, Reynolds A, et al. Melatonin Represses Metastasis in Her2-Postive Human Breast Cancer Cells by Suppressing RSK2 ExpressionMelatonin Represses Rsk of Breast Cancer Metastasis. Mol Cancer Res. 2016;14:1159–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wang SW, Tai HC, Tang CH, Lin LW, Lin TH, Chang AC, et al. Melatonin impedes prostate cancer metastasis by suppressing MMP-13 expression. J Cell Physiol. 2021;236:3979–90.

    Article  CAS  PubMed  Google Scholar 

  19. Dubocovich ML. Melatonin receptors: role on sleep and circadian rhythm regulation. Sleep Med. 2007;8:34–42.

    Article  PubMed  Google Scholar 

  20. Becker-André M, Wiesenberg I, Schaeren-Wiemers N, André E, Missbach M, Saurat J-H, et al. Pineal gland hormone melatonin binds and activates an orphan of the nuclear receptor superfamily. J Biol Chem. 1994;269:28531–4.

    Article  PubMed  Google Scholar 

  21. Ma H, Kang J, Fan W, He H, Huang F. ROR: Nuclear receptor for melatonin or not? Molecules. 2021;26:2693.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Boutin JA, Ferry G. Is there sufficient evidence that the melatonin binding site MT3 is quinone reductase 2? J Pharmacol Exp Ther. 2019;368:59–65.

    Article  CAS  PubMed  Google Scholar 

  23. Hunt AE, Al-Ghoul WM, Gillette MU, Dubocovich ML. Activation of MT2 melatonin receptors in rat suprachiasmatic nucleus phase advances the circadian clock. Am J Physiology-Cell Physiol. 2001;280:C110-C8.

    Article  Google Scholar 

  24. Jockers R, Maurice P, Boutin J, Delagrange P. Melatonin receptors, heterodimerization, signal transduction and binding sites: what’s new? Br J Pharmacol. 2008;154:1182–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Dubocovich ML, Markowska M. Functional MT1 and MT2 melatonin receptors in mammals. Endocrine. 2005;27:101–10.

    Article  CAS  PubMed  Google Scholar 

  26. Slominski RM, Reiter RJ, Schlabritz-Loutsevitch N, Ostrom RS, Slominski AT. Melatonin membrane receptors in peripheral tissues: distribution and functions. Mol Cell Endocrinol. 2012;351:152–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Capote-Moreno A, Ramos E, Egea J, López-Muñoz F, Gil-Martín E, Romero A. Potential of melatonin as adjuvant therapy of oral cancer in the era of epigenomics. Cancers. 2019;11:1712.

    Article  CAS  PubMed Central  Google Scholar 

  28. Cavalli G, Heard E. Advances in epigenetics link genetics to the environment and disease. Nature. 2019;571:489–99.

    Article  CAS  PubMed  Google Scholar 

  29. Moosavi A, Ardekani AM. Role of epigenetics in biology and human diseases. Iran Biomed J. 2016;20:246.

    PubMed  PubMed Central  Google Scholar 

  30. Bates SE. Epigenetic therapies for cancer. N Engl J Med. 2020;383:650–63.

    Article  CAS  PubMed  Google Scholar 

  31. Cheng Y, He C, Wang M, Ma X, Mo F, Yang S, et al. Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials. Signal Transduct Target therapy. 2019;4:1–39.

    Google Scholar 

  32. Surace AEA, Hedrich CM. The role of epigenetics in autoimmune/inflammatory disease. Frontiers in immunology. 2019:1525.

  33. Prasher D, Greenway SC, Singh RB. The impact of epigenetics on cardiovascular disease. Biochem Cell Biol. 2020;98:12–22.

    Article  CAS  PubMed  Google Scholar 

  34. Ling C, Rönn T. Epigenetics in human obesity and type 2 diabetes. Cell Metabol. 2019;29:1028–44.

    Article  CAS  Google Scholar 

  35. Klutstein M, Nejman D, Greenfield R, Cedar H. DNA Methylation in Cancer and Aging. Cancer Res. 2016;76:3446–50.

    Article  CAS  PubMed  Google Scholar 

  36. Angeloni A, Bogdanovic O. Sequence determinants, function, and evolution of CpG islands. Biochem Soc Trans. 2021;49:1109–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Carlberg C, Molnár F. Human epigenomics. Springer; 2018.

  38. Bird A. DNA methylation patterns and epigenetic memory. Genes Dev. 2002;16:6–21.

    Article  CAS  PubMed  Google Scholar 

  39. Reik W, Dean W, Walter J. Epigenetic reprogramming in mammalian development. Science. 2001;293:1089–93.

    Article  CAS  PubMed  Google Scholar 

  40. Kim M, Costello J. DNA methylation: an epigenetic mark of cellular memory. Exp Mol Med. 2017;49:e322-e. doi:https://doi.org/10.1038/emm.2017.10.

    Article  CAS  Google Scholar 

  41. Noroozi R, Ghafouri-Fard S, Pisarek A, Rudnicka J, Spólnicka M, Branicki W, et al. DNA methylation-based age clocks: from age prediction to age reversion. Ageing Res Rev. 2021;68:101314.

    Article  CAS  PubMed  Google Scholar 

  42. Skvortsova K, Stirzaker C, Taberlay P. The DNA methylation landscape in cancer. Essays Biochem. 2019;63:797–811.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wilson AG. Epigenetic regulation of gene expression in the inflammatory response and relevance to common diseases. J Periodontol. 2008;79:1514–9.

    Article  CAS  PubMed  Google Scholar 

  44. Magaña-Acosta M, Valadez-Graham V. Chromatin remodelers in the 3D nuclear compartment. Frontiers in Genetics. 2020:1344.

  45. Suzuki MM, Bird A. DNA methylation landscapes: provocative insights from epigenomics. Nat Rev Genet. 2008;9:465–76.

    Article  CAS  PubMed  Google Scholar 

  46. Ng H-H, Zhang Y, Hendrich B, Johnson CA, Turner BM, Erdjument-Bromage H, et al. MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex. Nat Genet. 1999;23:58–61.

    Article  CAS  PubMed  Google Scholar 

  47. Fouse SD, Nagarajan RP, Costello JF. Genome-scale DNA methylation analysis. Epigenomics. 2010;2:105–17.

    Article  CAS  PubMed  Google Scholar 

  48. Stoccoro A, Coppedè F. Mitochondrial DNA methylation and human diseases. Int J Mol Sci. 2021;22:4594.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ramsahoye BH, Biniszkiewicz D, Lyko F, Clark V, Bird AP, Jaenisch R. Non-CpG methylation is prevalent in embryonic stem cells and may be mediated by DNA methyltransferase 3a. Proceedings of the National Academy of Sciences. 2000;97:5237-42.

  50. Guo JU, Su Y, Shin JH, Shin J, Li H, Xie B, et al. Distribution, recognition and regulation of non-CpG methylation in the adult mammalian brain. Nat Neurosci. 2014;17:215–22.

    Article  CAS  PubMed  Google Scholar 

  51. Lister R, Mukamel EA, Nery JR, Urich M, Puddifoot CA, Johnson ND, et al. Global epigenomic reconfiguration during mammalian brain development. Science. 2013;341:1237905.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Udali S, De Santis D, Ruzzenente A, Moruzzi S, Mazzi F, Beschin G, et al. DNA methylation and hydroxymethylation in primary colon cancer and synchronous hepatic metastasis. Front Genet. 2018;8:229.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Cui H, Onyango P, Brandenburg S, Wu Y, Hsieh C-L, Feinberg AP. Loss of imprinting in colorectal cancer linked to hypomethylation of H19 and IGF2. Cancer Res. 2002;62:6442–6.

    CAS  PubMed  Google Scholar 

  54. Bjornsson HT, Brown LJ, Fallin MD, Rongione MA, Bibikova M, Wickham E, et al. Epigenetic specificity of loss of imprinting of the IGF2 gene in Wilms tumors. J Natl Cancer Inst. 2007;99:1270–3.

    Article  CAS  PubMed  Google Scholar 

  55. Gailhouste L, Liew LC, Yasukawa K, Hatada I, Tanaka Y, Kato T, et al. MEG3-derived miR-493-5p overcomes the oncogenic feature of IGF2-miR-483 loss of imprinting in hepatic cancer cells. Cell Death Dis. 2019;10:1–16.

    Article  CAS  Google Scholar 

  56. Murphy SK, Huang Z, Wen Y, Spillman MA, Whitaker RS, Simel LR, et al. Frequent IGF2/H19 domain epigenetic alterations and elevated IGF2 expression in epithelial ovarian cancer. Mol Cancer Res. 2006;4:283–92.

    Article  CAS  PubMed  Google Scholar 

  57. Ulaner GA, Vu TH, Li T, Hu J-F, Yao X-M, Yang Y, et al. Loss of imprinting of IGF2 and H19 in osteosarcoma is accompanied by reciprocal methylation changes of a CTCF-binding site. Hum Mol Genet. 2003;12:535–49.

    Article  CAS  PubMed  Google Scholar 

  58. Vu TH, Nguyen AH, Hoffman AR. Loss of IGF2 imprinting is associated with abrogation of long-range intrachromosomal interactions in human cancer cells. Hum Mol Genet. 2010;19:901–19.

    Article  CAS  PubMed  Google Scholar 

  59. Leick MB, Shoff CJ, Wang EC, Congress JL, Gallicano GI. Loss of imprinting of IGF2 and the epigenetic progenitor model of cancer. Am J stem cells. 2012;1:59.

    CAS  PubMed  Google Scholar 

  60. Bhusari S, Yang B, Kueck J, Huang W, Jarrard DF. Insulin-like growth factor‐2 (IGF2) loss of imprinting marks a field defect within human prostates containing cancer. Prostate. 2011;71:1621–30.

    Article  CAS  PubMed  Google Scholar 

  61. Feinberg AP, Koldobskiy MA, Göndör A. Epigenetic modulators, modifiers and mediators in cancer aetiology and progression. Nat Rev Genet. 2016;17:284–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Timp W, Feinberg AP. Cancer as a dysregulated epigenome allowing cellular growth advantage at the expense of the host. Nat Rev Cancer. 2013;13:497–510.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Jeschke J, Collignon E, Fuks F. Portraits of TET-mediated DNA hydroxymethylation in cancer. Curr Opin Genet Dev. 2016;36:16–26.

    Article  CAS  PubMed  Google Scholar 

  64. Huang Y, Rao A. Connections between TET proteins and aberrant DNA modification in cancer. Trends Genet. 2014;30:464–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Wright JB, Brown SJ, Cole MD. Upregulation of c-MYC in cis through a large chromatin loop linked to a cancer risk-associated single-nucleotide polymorphism in colorectal cancer cells. Mol Cell Biol. 2010;30:1411–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Ye Q, Hu Y-F, Zhong H, Nye AC, Belmont AS, Li R. BRCA1-induced large-scale chromatin unfolding and allele-specific effects of cancer-predisposing mutations. J Cell Biol. 2001;155:911–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Khalili-Tanha G, Moghbeli M. Long non-coding RNAs as the critical regulators of doxorubicin resistance in tumor cells. Cell Mol Biol Lett. 2021;26:1–25.

    Article  CAS  Google Scholar 

  68. Homayoonfal M, Asemi Z, Yousefi B. Potential anticancer properties and mechanisms of thymoquinone in osteosarcoma and bone metastasis. Cell Mol Biol Lett. 2022;27:21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Homayoonfal M, Asemi Z, Yousefi B. Targeting microRNAs with thymoquinone: a new approach for cancer therapy. Cell Mol Biol Lett. 2021;26:43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Muñoz P, Iliou MS, Esteller M. Epigenetic alterations involved in cancer stem cell reprogramming. Mol Oncol. 2012;6:620–36.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Paksa A, Rajagopal J. The epigenetic basis of cellular plasticity. Curr Opin Cell Biol. 2017;49:116–22.

    Article  CAS  PubMed  Google Scholar 

  72. de Unamuno Bustos B, Murria Estal R, Pérez Simó G, Simarro Farinos J, Pujol Marco C, Navarro Mira M, et al. Aberrant DNA methylation is associated with aggressive clinicopathological features and poor survival in cutaneous melanoma. Br J Dermatol. 2018;179:394–404.

    PubMed  Google Scholar 

  73. Sakaguchi H, Muramatsu H, Okuno Y, Makishima H, Xu Y, Furukawa-Hibi Y, et al. Aberrant DNA methylation is associated with a poor outcome in juvenile myelomonocytic leukemia. PLoS ONE. 2015;10:e0145394.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Zhang Z, Hu X, Kuang J, Liao J, Yuan Q. LncRNA DRAIC inhibits proliferation and metastasis of gastric cancer cells through interfering with NFRKB deubiquitination mediated by UCHL5. Cell Mol Biol Lett. 2020;25:1–17.

    Article  Google Scholar 

  75. Galli R, Binda E, Orfanelli U, Cipelletti B, Gritti A, De Vitis S, et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res. 2004;64:7011–21.

    Article  CAS  PubMed  Google Scholar 

  76. Charles N, Holland EC. Brain tumor treatment increases the number of cancer stem-like cells. Expert Rev Neurother. 2009;9:1447–9.

    Article  PubMed  Google Scholar 

  77. Martín V, Sanchez-Sanchez AM, Herrera F, Gomez-Manzano C, Fueyo J, Alvarez-Vega MA, et al. Melatonin-induced methylation of the ABCG2/BCRP promoter as a novel mechanism to overcome multidrug resistance in brain tumour stem cells. Br J Cancer. 2013;108:2005–12.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Bondy SC, Campbell A. Mechanisms underlying tumor suppressive properties of melatonin. Int J Mol Sci. 2018;19:2205.

    Article  PubMed Central  CAS  Google Scholar 

  79. Mannino G, Caradonna F, Cruciata I, Lauria A, Perrone A, Gentile C. Melatonin reduces inflammatory response in human intestinal epithelial cells stimulated by interleukin-1β. J Pineal Res. 2019;67:e12598.

    Article  PubMed  CAS  Google Scholar 

  80. Boyle P, Levin B. World cancer report 2008. IARC Press, International Agency for Research on Cancer; 2008.

  81. Stevens RG. Light-at-night, circadian disruption and breast cancer: assessment of existing evidence. Int J Epidemiol. 2009;38:963–70.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Schernhammer ES, Laden F, Speizer FE, Willett WC, Hunter DJ, Kawachi I, et al. Rotating night shifts and risk of breast cancer in women participating in the nurses’ health study. J Natl Cancer Inst. 2001;93:1563–8.

    Article  CAS  PubMed  Google Scholar 

  83. Schwimmer H, Metzer A, Pilosof Y, Szyf M, Machnes ZM, Fares F, et al. Light at night and melatonin have opposite effects on breast cancer tumors in mice assessed by growth rates and global DNA methylation. Chronobiol Int. 2014;31:144–50.

    Article  CAS  PubMed  Google Scholar 

  84. Lee SE, Kim SJ, Yoon HJ, Yu SY, Yang H, Jeong SI, et al. Genome-wide profiling in melatonin‐exposed human breast cancer cell lines identifies differentially methylated genes involved in the anticancer effect of melatonin. J Pineal Res. 2013;54:80–8.

    Article  CAS  PubMed  Google Scholar 

  85. Agbaria S, Haim A, Fares F, Zubidat AE. Epigenetic modification in 4T1 mouse breast cancer model by artificial light at night and melatonin–the role of DNA-methyltransferase. Chronobiol Int. 2019;36:629–43.

    Article  CAS  PubMed  Google Scholar 

  86. Sadoughi F, Dana PM, Asemi Z, Shafabakhash R, Mohammadi S, Heidar Z, et al. Molecular and cellular mechanisms of melatonin in breast cancer. Biochimie. 2022.

  87. Wang T, Fahrmann JF, Lee H, Li Y-J, Tripathi SC, Yue C, et al. JAK/STAT3-regulated fatty acid β-oxidation is critical for breast cancer stem cell self-renewal and chemoresistance. Cell Metabol. 2018;27:136–50. e5.

    Article  CAS  Google Scholar 

  88. Karami Fath M, Azargoonjahromi A, Kiani A, Jalalifar F, Osati P, Akbari Oryani M, et al. The role of epigenetic modifications in drug resistance and treatment of breast cancer. Cell Mol Biol Lett. 2022;27:1–25.

    Article  CAS  Google Scholar 

  89. Kohandel Z, Farkhondeh T, Aschner M, Pourbagher-Shahri AM, Samarghandian S. STAT3 pathway as a molecular target for resveratrol in breast cancer treatment. Cancer Cell Int. 2021;21:1–9.

    Article  CAS  Google Scholar 

  90. Xiang S, Dauchy RT, Hoffman AE, Pointer D, Frasch T, Blask DE, et al. Epigenetic inhibition of the tumor suppressor ARHI by light at night-induced circadian melatonin disruption mediates STAT3‐driven paclitaxel resistance in breast cancer. J Pineal Res. 2019;67:e12586.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Ren Z, He H, Zuo Z, Xu Z, Wei Z, Deng J. The role of different SIRT1-mediated signaling pathways in toxic injury. Cell Mol Biol Lett. 2019;24:1–10.

    Article  Google Scholar 

  92. Rybnikova N, Portnov BA. Population-level study links short-wavelength nighttime illumination with breast cancer incidence in a major metropolitan area. Chronobiol Int. 2018;35:1198–208.

    Article  PubMed  Google Scholar 

  93. Zubidat AE, Fares B, Fares F, Haim A. Artificial Light at Night of Different Spectral Compositions Differentially Affects Tumor Growth in Mice: Interaction With Melatonin and Epigenetic Pathways. Cancer control: journal of the Moffitt Cancer Center. 2018;25:1073274818812908. 

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

Not applicable.

Author information

Authors and Affiliations

Authors

Contributions

AD, BN, RJR, and ZA contributed to the concept, design, drafting and editing of the manuscript. All authors approved the submitted version of the manuscript.

Corresponding author

Correspondence to Zatollah Asemi.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Davoodvandi, A., Nikfar, B., Reiter, R.J. et al. Melatonin and cancer suppression: insights into its effects on DNA methylation. Cell Mol Biol Lett 27, 73 (2022). https://doi.org/10.1186/s11658-022-00375-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s11658-022-00375-z

Keywords