The dynamic and static modification of the epigenome by hormones: A role in the developmental origin of hormone related cancers

There are numerous diseases associated with abnormal hormonal regulation and these include cancers of the breast and prostate. There is substantial evidence that early hormonal perturbations (in utero or during early development) are associated with increased disease susceptibility later in life. These perturbations may arise from exposure to environmental agents or endocrine disruptors which mimic hormones and disrupt normal hormonal signaling. Epigenetic alterations have often been proposed as the underlying mechanism by which early hormonal perturbations may give rise to disease in adulthood. Currently, there is minimal evidence to support a direct link between early hormonal perturbations and epigenetic modifications; or between epigenetic alterations and subsequent onset of cancer. Given that epigenetic modifications may play an important role in hormone-dependent cancers, it is essential to better understand the relationship between the hormonal environment and epigenetic modifications in both normal and disease states. In this review, we highlight several important studies which support the hypothesis that: hormonal perturbations early in life may result in epigenetic changes that may modify hormone receptor function, thereby contributing to an increased risk of developing hormone-related cancers.     

Nocturnal light pollution and underexposure to daytime sunlight: Complementary mechanisms of circadian disruption and related diseases

Routine exposure to artificial light at night (ALAN) in work, home, and community settings is linked with increased risk of breast and prostate cancer (BC, PC) in normally sighted women and men, the hypothesized biological rhythm mechanisms being frequent nocturnal melatonin synthesis suppression, circadian time structure (CTS) desynchronization, and sleep/wake cycle disruption with sleep deprivation. ALAN-induced perturbation of the CTS melatonin synchronizer signal is communicated maternally at the very onset of life and after birth via breast or artificial formula feedings. Nighttime use of personal computers, mobile phones, electronic tablets, televisions, and the like – now epidemic in adolescents and adults and highly prevalent in pre-school and school-aged children – is a new source of ALAN. However, ALAN exposure occurs concomitantly with almost complete absence of daytime sunlight, whose blue-violet (446–484?nm λ) spectrum synchronizes the CTS and whose UV-B (290–315?nm λ) spectrum stimulates vitamin D synthesis. Under natural conditions and clear skies, day/night and annual cycles of UV-B irradiation drive corresponding periodicities in vitamin D synthesis and numerous bioprocesses regulated by active metabolites augment and strengthen the biological time structure. Vitamin D insufficiency and deficiency are widespread in children and adults in developed and developing countries as a consequence of inadequate sunlight exposure. Past epidemiologic studies have focused either on exposure to too little daytime UV-B or too much ALAN, respectively, on vitamin D deficiency/insufficiency or melatonin suppression in relation to risk of cancer and other, e.g., psychiatric, hypertensive, cardiac, and vascular, so-called, diseases of civilization. The observed elevated incidence of medical conditions the two are alleged to influence through many complementary bioprocesses of cells, tissues, and organs led us to examine effects of the totality of the artificial light environment in which humans reside today. Never have chronobiologic or epidemiologic investigations comprehensively researched the potentially deleterious consequences of the combination of suppressed vitamin D plus melatonin synthesis due to life in today’s man-made artificial light environment, which in our opinion is long overdue.     

Epigenetic modification in 4T1 mouse breast cancer model by artificial light at night and melatonin – the role of DNA-methyltransferase

Currently, one of the most disputed hypotheses regarding breast cancer (BC) development is exposure to short wavelength artificial light at night (ALAN) as multiple studies suggest a possible link between them. This link is suggested to be mediated by nocturnal melatonin suppression that plays an integral role in circadian regulations including cell division. The objective of the research was to evaluate effects of 1 × 30 min/midnight ALAN (134 µ Wcm^?2, 460 nm) with or without nocturnal melatonin supplement on tumor development and epigenetic responses in 4T1 tumor-bearing BALB/c mice. Mice were monitored for body mass (W_b) and tumor volume for 3 weeks and thereafter urine samples were collected at regular intervals for determining daily rhythms of 6-sulfatoxymelatonin (6-SMT). Finally, mice were sacrificed and the tumor, lungs, liver, and spleen were excised for analyzing the total activity of DNA methyltransferases (DNMT) and global DNA methylation (GDM) levels. Mice exposed to ALAN significantly reduced 6-SMT levels and increased W_b, tumor volume, and lung metastasis compared with controls. These effects were diminished by melatonin. The DNMT activity and GDM levels showed tissue-specific response. The enzymatic activity and GDM levels were lower in tumor and liver and higher in spleen and lungs under ALAN compared with controls. Our results suggest that ALAN disrupts the melatonin rhythm and potentially leading to increased BC burden by affecting DNMT activity and GDM levels. These data may also be applicable to early detection and management of BC by monitoring melatonin and GDM levels as early biomarker of ALAN circadian disruption.     

Melatonin mends adverse temporal effects of bright light at night partially independent of its effect on stress responses in captive birds

ABSTRACT

Ecological artificial light at night (ALAN) has been increasingly associated with negative effects on the behavior and ecology of wild birds. However, the impacts of short-term bright ALAN on the temporal biology of companion animals and the underlying mediating mechanism are unknown. We evaluated impacts of 1X60-min/middle night ALAN (200 lux, λ_Dominant = 460 nm) nightly with or without melatonin administration on growth performance, reproductive capacity, food and water intake, and stress responses in Australian budgerigars (Melopsittacus undulatus) under captivity. 36 birds were housed in pairs under natural photoperiod and were equally divided into three groups: control, natural conditions; ALAN, control + ALAN; and melatonin, ALAN + melatonin in the drinking water during the dark period. Birds were regularly monitored for body mass, egg production, and hatchability over four months. Food intake, water consumption, and daily rhythm of fecal corticosterone were also evaluated. ALAN increased mass gain, food intake, water consumption, and drastically decreased reproductive capacity, whereas stress responses were markedly augmented. Melatonin restored food and water intake to control levels but partly reversed mass gain. Melatonin failed to ameliorate the impaired reproductive capacity despite reducing the stress responses to basal levels. These results suggest that the ALAN-induced negative impacts cannot be attributed solely to direct effects of melatonin suppression or/and exacerbated stress responses and the involvement of other photoperiodic pathway components warrant further studies. Finally, the results of our study may be of importance for improving the housing conditions of companion animals at least as concern bright ALAN exposures.     

Epigenetic gene silencing in the Wnt pathway in breast cancer

Breast cancer is one of the most common malignancies in women. Despite advances in treatment of endocrine-dependent tumors, the complete molecular basis of transformation is still unknown. What is clear is that a variety of genetic lesions and epigenetic modifications are present in the neoplasm. Disregulation of several signaling pathways is known to be associated with breast cancer development, among them is the wingless and integration site growth factor (Wnt) pathway. While genetic mutations of certain components of this pathway, such as APC, are significant contributing factors for colorectal cancers, they are typically not the predominate mechanism associated with breast cancer. Instead, it appears that DNA hypermethylation leads to aberrant regulation of the Wnt pathway in breast cancer, and as such, this review focuses on the epigenetic regulation of Wnt pathway components in breast cancer.     

Light at night and melatonin have opposite effects on breast cancer tumors in mice assessed by growth rates and global DNA methylation

Light-at-night (LAN) is a worldwide problem co-distributed with breast cancer prevalence. We hypothesized that exposure to LAN is coincided with a decreased melatonin (MLT) secretion level, followed by epigenetic modifications and resulted in higher breast cancer tumors growth-rate. Accordingly, we studied the effect of LAN exposure and exogenous MLT on breast cancer tumors growth-rate. 4T1 cells were inoculated into BALB/c short day-acclimated mice, resulting in tumors growth. Growth rates were followed under various light exposures and global DNA methylations were measured. Results demonstrated the positive effect of LAN on tumors growth-rate, reversed by MLT through global DNA methylation.     

Perturbateurs endocriniens environnementaux et cancers hormonodépendants. De nouveaux facteurs de risque ?

The involvement of environmental endocrine disruptors (EED) in hormone dependent carcinogenesis is supported by: (1) in utero exposure to distilbene, a human experimental model which led to vaginal adenocarcinoma in the young daughter and an increased risk of breast cancer after 40 years; (2) epidemiological case/control studies showing although many confounders and methodological biais, a correlation between blood, adipose tissue or tumoral EED levels and hormone dependent cancers (breast cancer and PCB, PAH and dioxine levels; prostate cancer and chlordecone levels; testicular germ cell cancer and of PCB, HCB or chlordane blood levels of the mothers); (3) experimental models able to induce in rodents after fetal or perinatal exposure to diéthylstilbestrol (DES), bisphenol A or atrazine, adult breast or prostate cancers; (4) in vitro malignant cell studies showing how EEDs like bisphenol A are able to interfere with prostate, breast or testicular germ cell proliferation, apoptosis and survey. All these reports suggest a reassessment of EED chemotoxicity during carcinogenesis which needs to include low doses of EEDs with additive or synergistic mixture during critical windows of exposure such as fetal or perinatal periods leading to stable epigenetic modifications which do not change the genetic code but may participate to the malignant transformation and/or promotion.     

One-carbon metabolism and Alzheimer's disease: focus on epigenetics

Alzheimer's disease (AD) represents the most common form of dementia in the elderly, characterized by progressive loss of memory and cognitive capacity severe enough to interfere with daily functioning and the quality of life. Rare, fully penetrant mutations in three genes (APP, PSEN1 and PSEN2) are responsible for familial forms of the disease. However, more than 90% of AD is sporadic, likely resulting from complex interactions between genetic and environmental factors. Increasing evidence supports a role for epigenetic modifications in AD pathogenesis. Folate metabolism, also known as one-carbon metabolism, is required for the production of S-adenosylmethionine (SAM), which is the major DNA methylating agent. AD individuals are characterized by decreased plasma folate values, as well as increased plasma homocysteine (Hcy) levels, and there is indication of impaired SAM levels in AD brains. Polymorphisms of genes participating in one-carbon metabolism have been associated with AD risk and/or with increased Hcy levels in AD individuals. Studies in rodents suggest that early life exposure to neurotoxicants or dietary restriction of folate and other B vitamins result in epigenetic modifications of AD related genes in the animal brains. Similarly, studies performed on human neuronal cell cultures revealed that folate and other B vitamins deprivation from the media resulted in epigenetic modification of the PSEN1 gene. There is also evidence of epigenetic modifications in the DNA extracted from blood and brains of AD subjects. Here I review one-carbon metabolism in AD, with emphasis on possible epigenetic consequences.     

Epigenetic regulation of prostate cancer

Prostate cancer is a commonly diagnosed cancer in men and a leading cause of cancer deaths. Whilst the underlying mechanisms leading to prostate cancer are still to be determined, it is evident that both genetic and epigenetic changes contribute to the development and progression of this disease. Epigenetic changes involving DNA hypo- and hypermethylation, altered histone modifications and more recently changes in microRNA expression have been detected at a range of genes associated with prostate cancer. Furthermore, there is evidence that particular epigenetic changes are associated with different stages of the disease. Whilst early detection can lead to effective treatment, and androgen deprivation therapy has a high response rate, many tumours develop towards hormone-refractory prostate cancer, for which there is no successful treatment. Reliable markers for early detection and more effective treatment strategies are, therefore, needed. Consequently, there is a considerable interest in the potential of epigenetic changes as markers or targets for therapy in prostate cancer. Epigenetic modifiers that demethylate DNA and inhibit histone deacetylases have recently been explored to reactivate silenced gene expression in cancer. However, further understanding of the mechanisms and the effects of chromatin modulation in prostate cancer are required. In this review, we examine the current literature on epigenetic changes associated with prostate cancer and discuss the potential use of epigenetic modifiers for treatment of this disease.     

Environmental epigenetics in metal exposure

Although it is widely accepted that chronic exposure to arsenite, nickel, chromium and cadmium increases cancer incidence in individuals, the molecular mechanisms underlying their ability to transform cells remain largely unknown. Carcinogenic metals are typically weak mutagens, suggesting that genetic-based mechanisms may not be primarily responsible for metal-induced carcinogenesis. Growing evidence shows that environmental metal exposure involves changes in epigenetic marks, which may lead to a possible link between heritable changes in gene expression and disease susceptibility and development. Here, we review recent advances in the understanding of metal exposure affecting epigenetic marks and discuss establishment of heritable gene expression in metal-induced carcinogenesis.Key words: environmental metal, epigenetic, metal carcinogenesis, histone modification, DNA methylation, chromatin, gene expression     

Environmental epigenetics in metal exposure

Although it is widely accepted that chronic exposure to arsenite, nickel, chromium and cadmium increases cancer incidence in individuals, the molecular mechanisms underlying their ability to transform cells remain largely unknown. Carcinogenic metals are typically weak mutagens, suggesting that genetic-based mechanisms may not be primarily responsible for metal-induced carcinogenesis. Growing evidence shows that environmental metal exposure involves changes in epigenetic marks, which may lead to a possible link between heritable changes in gene expression and disease susceptibility and development. Here, we review recent advances in the understanding of metal exposure affecting epigenetic marks and discuss establishment of heritable gene expression in metal-induced carcinogenesis.     

One-carbon metabolism and breast cancer: an epidemiological perspective

One-carbon metabolism is a network of biological reactions that plays critical role in DNA methylation and DNA synthesis, and in turn, facilitates the cross-talk between genetic and epigenetic processes. Genetic polymorphisms and supplies of cofactors （e.g. folate, vitamins B） involved in this pathway have been shown to influence cancer risk and even survival. In this review, we summarized the epidemiological evidence for one-carbon metabolism, from both genetics and lifestyle aspects, in relation to breast cancer risk. We also discussed this pathway in relation to breast cancer survival and the modulation of one-carbon polymorphism in chemotherapy. Emerging evidence on modulation of DNA methylation by one-carbon metabolism suggests that disruption of epigenome might have been the underlying mechanism. More results are expected and will be translated to guidance to the general population for disease prevention as well as to clinicians for treatment and management of the disease.     

Genetic Determinants of Epigenetic Patterns: Providing Insight into Disease

The field of epigenetics and our understanding of the mechanisms that regulate the establishment, maintenance and heritability of epigenetic patterns continue to grow at a remarkable rate. This information is providing increased understanding of the role of epigenetic changes in disease, insight into the underlying causes of these epigenetic changes and revealing new avenues for therapeutic intervention. Epigenetic modifiers are increasingly being pursued as therapeutic targets in a range of diseases, with a number of agents targeting epigenetic modifications already proving effective in diseases such as cancer. Although it is well established that DNA mutations and aberrant expression of epigenetic modifiers play a key role in disease, attention is now turning to the interplay between genetic and epigenetic factors in complex disease etiology. The role of genetic variability in determining epigenetic profiles, which can then be modified by environmental and stochastic factors, is becoming more apparent. Understanding the interplay between genetic and epigenetic factors is likely to aid in identifying individuals most likely to benefit from epigenetic therapies. This goal is coming closer to realization because of continual advances in laboratory and statistical tools enabling improvements in the integration of genomic, epigenomic and phenotypic data.     

Environmental epigenomics and disease susceptibility

Epidemiological evidence increasingly suggests that environmental exposures early in development have a role in susceptibility to disease in later life. In addition, some of these environmental effects seem to be passed on through subsequent generations. Epigenetic modifications provide a plausible link between the environment and alterations in gene expression that might lead to disease phenotypes. An increasing body of evidence from animal studies supports the role of environmental epigenetics in disease susceptibility. Furthermore, recent studies have demonstrated for the first time that heritable environmentally induced epigenetic modifications underlie reversible transgenerational alterations in phenotype. Methods are now becoming available to investigate the relevance of these phenomena to human disease.     

Epigenetic-based therapy for colorectal cancer: Prospect and involved mechanisms

Epigenetic modifications are heritable variations in gene expression not encoded by the DNA sequence. According to reports, a large number of studies have been performed to characterize epigenetic modification during normal development and also in cancer. Epigenetics can be regarded more widely to contain all of the changes in expression of genes that make by adjusted interactions between the regulatory portions of DNA or messenger RNAs that lead to indirect variation in the DNA sequence. In the last decade, epigenetic modification importance in colorectal cancer (CRC) pathogenesis was demonstrated powerfully. Although developments in CRC therapy have been made in the last years, much work is required as it remains the second leading cause of cancer death. Nowadays, epigenetic programs and genetic change have pivotal roles in the CRC incidence as well as progression. While our knowledge about epigenetic mechanism in CRC is not comprehensive, selective histone modifications and resultant chromatin conformation together with DNA methylation most likely regulate CRC pathogenesis that involved genes expression. Undoubtedly, the advanced understanding of epigenetic-based gene expression regulation in the CRC is essential to make epigenetic drugs for CRC therapy. The major aim of this review is to deliver a summary of valuable results that represent evidence of principle for epigenetic-based therapeutic approaches employment in CRC with a focus on the advantages of epigenetic-based therapy in the inhibition of the CRC metastasis and proliferation.     

The association between artificial light at night and prostate cancer in Gwangju City and South Jeolla Province of South Korea

Exposure to artificial light at night (ALAN) has been reported to be associated with various pathological changes including sleep deprivation, circadian rhythm disruption, and melatonin suppression with increase in various cancers such as breast or prostate cancers. In this study, we sought to elucidate the association between ALAN and prostate cancer in 27 districts within Gwangju City and urban and rural areas from South Jeolla Province in South Korea. We analyzed the correlation between ALAN and the incidence of a range of cancers by Poisson regression analysis, after adjustment for confounding risk factors, such as smoking, drinking, obesity, stress, air pollution (particulate matter <10 μm in diameter), urbanization (proportion of urbanized area), and the cancer screening rate. Interestingly, the incidence of prostate cancer was significantly associated with ALAN (risk ratio = 1.02, p = 0.0369) and urbanization (risk ratio = 1.06, p = 0.0055). In particular, comparing the prostate cancer incidence at 25% and 75% level of ALAN, the risk ratio was 1.726 (12.6 over 7.3, respectively). No significant association was observed between ALAN and other cancers, including stomach, esophageal, liver, pancreatic, laryngeal, lung and tracheal, bladder, and brain and central nervous system cancers, as well as lymphoma and multiple myeloma. In conclusion, this study shows that a high incidence of prostate cancer may be independently associated with light pollution and urbanization, which represent significant factors in the rapid process of industrialization of South Korea.     

Genetic and Epigenetic Regulation of TOX3 Expression in Breast Cancer

Genome wide association studies (GWAS) have identified low penetrance and high frequency single nucleotide polymorphisms (SNPs) that contribute to genetic susceptibility of breast cancer. The SNPs at 16q12, close to the TOX3 and CASC16 genes, represent one of the susceptibility loci identified by GWAS, showing strong evidence for breast cancer association across various populations. To examine molecular mechanisms of TOX3 regulation in breast cancer, we investigated both genetic and epigenetic factors using cell lines and datasets derived from primary breast tumors available through The Cancer Genome Atlas (TCGA). TOX3 expression is highly up-regulated in luminal subtype tumors compared to normal breast tissues or basal-like tumors. Expression quantitative trait loci (eQTL) analyses revealed significant associations of rs3803662 and rs4784227 genotypes with TOX3 expression in breast tumors. Bisulfite sequencing of four CpG islands in the TOX3 promoter showed a clear difference between luminal and basal-like cancer cell lines. 5-Aza-2’-deoxycytidine treatment of a basal-like cancer cell line increased expression of TOX3. TCGA dataset verified significantly lower levels of methylation of the promoter in luminal breast tumors with an inverse correlation between methylation and expression of TOX3. Methylation QTL (mQTL) analyses showed a weak or no correlation of rs3803662 or rs4784227 with TOX3 promoter methylation in breast tumors, indicating an independent relationship between the genetic and epigenetic events. These data suggest a complex system of TOX3 regulation in breast tumors, driven by germline variants and somatic epigenetic modifications in a subtype specific manner.     

Melatonin: A new inhibitor agent for cervical cancer treatment

Cervical cancer is one of the most common cancers between women and is known as the third leading cause of female cancer related deaths annually. Its detection in early stages allows it to be a preventable and generally treatable disease. Increasing evidence revealed, a variety of internal and external factors are associated with initiation and progression of cervical cancer pathogenesis. Human papilloma virus infection is found as a major cause of cervical cancer. Other molecular and biochemical alterations as well as genetic and epigenetic changes are related cervical cancer progression. Current treatment options often have severe side effects and toxicities thus, new adjuvant agents having synergistic effects and ability to decrease different side effects and toxicities are needed. Melatonin is an indolamine compound secreted from the pineal gland which shows wide range anticancer activities. A large amount of studies indicated inhibitory effects of melatonin against various types of cancers. In addition, experimental evidence reports inhibitory effects of melatonin as an adjuvant therapy on cervical cancer by targeting a sequence of different molecular mechanisms. Herein, for first time, we summarized anticervical cancer effects of melatonin and its underlying molecular mechanisms.