Methyl Donor Micronutrients that Modify DNA Methylation and Cancer Outcome

DNA methylation is an epigenetic mechanism that is essential for regulating gene transcription. However, aberrant DNA methylation, which is a nearly universal finding in cancer, can result in disturbed gene expression. DNA methylation is modified by environmental factors such as diet that may modify cancer risk and tumor behavior. Abnormal DNA methylation has been observed in several cancers such as colon, stomach, cervical, prostate, and breast cancers. These alterations in DNA methylation may play a critical role in cancer development and progression. Dietary nutrient intake and bioactive food components are essential environmental factors that may influence DNA methylation either by directly inhibiting enzymes that catalyze DNA methylation or by changing the availability of substrates required for those enzymatic reactions such as the availability and utilization of methyl groups. In this review, we focused on nutrients that act as methyl donors or methylation co-factors and presented intriguing evidence for the role of these bioactive food components in altering DNA methylation patterns in cancer. Such a role is likely to have a mechanistic impact on the process of carcinogenesis and offer possible therapeutic potentials.

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Thrombomodulin Is Silenced in Malignant Mesothelioma by a Poly(ADP-ribose) Polymerase-1-mediated Epigenetic Mechanism

Journal of Biological Chemistry ◽

10.1074/jbc.m110.217331 ◽

2011 ◽

Vol 286 (22) ◽

pp. 19478-19488 ◽

Cited By ~ 18

Author(s):

Linda Nocchi ◽

Marco Tomasetti ◽

Monica Amati ◽

Jiri Neuzil ◽

Lory Santarelli ◽

...

Keyword(s):

Dna Methylation ◽

Malignant Mesothelioma ◽

Promoter Methylation ◽

Dna Methyltransferase ◽

Critical Role ◽

Gene Promoter ◽

Epigenetic Mechanism ◽

Heterogeneous Expression ◽

High Level

Malignant mesothelioma (MM) is often complicated by thromboembolic episodes, with thrombomodulin (TM) playing a critical role in the anticoagulant process. Heterogeneous expression of TM has been observed in cancer, and low or no TM expression in cancer cells is associated with poor prognosis. In this study, we analyzed TM expression in biopsies of MM patients and compared them with normal mesothelial tissue. The role of DNA methylation-associated gene silencing in TM expression was investigated. To evaluate poly(ADP-ribose) polymerase-1 (PARP1) as responsible for gene promoter epigenetic modifications, nonmalignant mesothelial cells (Met-5A) and MM cells (H28) were silenced for PARP1 and the DNA methylation/acetylation-associated TM expression evaluated. A correlation between low TM expression and high level of TM promoter methylation was found in MM biopsies. Low expression of TM was restored in MM cells by their treatment with 5-aza-2′-deoxycytidine and, to a lesser extent, with trichostatin, whereas the epigenetic agents did not affect TM expression in Met-5A cells. Silencing of PARP1 resulted in a strong down-regulation of TM expression in Met-5A cells, while restoring TM expression in H28 cells. PARP1 silencing induced TM promoter methylation in Met-5A cells and demethylation in MM cells, and this was paralleled by corresponding changes in the DNA methyltransferase activity. We propose that methylation of the TM promoter is responsible for silencing of TM expression in MM tissue, a process that is regulated by PARP1.

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Maternal nutritional status, C1 metabolism and offspring DNA methylation: a review of current evidence in human subjects

Proceedings of The Nutrition Society ◽

10.1017/s0029665111003338 ◽

2011 ◽

Vol 71 (1) ◽

pp. 154-165 ◽

Cited By ~ 95

Author(s):

Paula Dominguez-Salas ◽

Sharon E. Cox ◽

Andrew M. Prentice ◽

Branwen J. Hennig ◽

Sophie E. Moore

Keyword(s):

Dna Methylation ◽

Human Subjects ◽

In Utero ◽

Neural Tube Closure ◽

Epigenetic Mechanism ◽

Current Evidence ◽

Long Term Effects ◽

Folate Supplementation ◽

Methyl Donors ◽

C1 Metabolism

Evidence is growing for the long-term effects of environmental factors during early-life on later disease susceptibility. It is believed that epigenetic mechanisms (changes in gene function not mediated by DNA sequence alteration), particularly DNA methylation, play a role in these processes. This paper reviews the current state of knowledge of the involvement of C1 metabolism and methyl donors and cofactors in maternal diet-induced DNA methylation changes in utero as an epigenetic mechanism. Methyl groups for DNA methylation are mostly derived from the diet and supplied through C1 metabolism by way of choline, betaine, methionine or folate, with involvement of riboflavin and vitamins B6 and B12 as cofactors. Mouse models have shown that epigenetic features, for example DNA methylation, can be altered by periconceptional nutritional interventions such as folate supplementation, thereby changing offspring phenotype. Evidence of early nutrient-induced epigenetic change in human subjects is scant, but it is known that during pregnancy C1 metabolism has to cope with high fetal demands for folate and choline needed for neural tube closure and normal development. Retrospective studies investigating the effect of famine or season during pregnancy indicate that variation in early environmental exposure in utero leads to differences in DNA methylation of offspring. This may affect gene expression in the offspring. Further research is needed to examine the real impact of maternal nutrient availability on DNA methylation in the developing fetus.

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Epigenetic activation of the prostaglandin receptor EP4 promotes resistance to endocrine therapy for breast cancer

10.1101/056770 ◽

2016 ◽

Author(s):

Jeffrey F. Hiken ◽

James I. McDonald ◽

Keith F. Decker ◽

Cesar Sanchez ◽

Jeremy Hoog ◽

...

Keyword(s):

Breast Cancer ◽

Dna Methylation ◽

Estrogen Receptor ◽

Endocrine Therapy ◽

Cancer Recurrence ◽

Therapy Resistance ◽

Epigenetic Mechanism ◽

Prostaglandin E ◽

Breast Cancers ◽

Estrogen Production

AbstractApproximately 75% of breast cancers express estrogen receptor α (ERα) and depend on estrogen signals for continued growth. Aromatase inhibitors (AIs) prevent estrogen production and inhibit estrogen receptor signaling, resulting in decreased cancer recurrence and mortality. Advanced tumors treated with AIs almost always develop resistance to these drugs via the up-regulation of alternative growth signals. The mechanisms that drive this resistance—especially epigenetic events that alter gene expression—are however not well understood. Genome-wide DNA methylation and expression analysis of cell line models of acquired aromatase inhibitor resistance indicated that prostaglandin E2 receptor 4 (PTGER4) is up-regulated after demethylation in resistant cells. Knockdown and inhibitor studies demonstrate that PTGER4 is essential for estrogen independent growth. Analysis of downstream signaling indicates that PTGER4 likely promotes AI resistance via ligand independent activation of the ERα-cofactor CARM1. We believe that we have discovered a novel epigenetic mechanism for altering cell signaling and acquiring endocrine therapy resistance. Our findings indicate that PTGER4 is a potential drug target in AI resistant cancers. Additionally, the epigenetic component of PTGER4 regulation suggests that further study of PTGER4 may yield valuable insights into how DNA methylation-targeted diagnoses and treatments can improve AI resistant breast cancer treatment.

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Epigenetic Changes Induced by Maternal Factors during Fetal Life: Implication for Type 1 Diabetes

Genes ◽

10.3390/genes12060887 ◽

2021 ◽

Vol 12 (6) ◽

pp. 887

Author(s):

Ilaria Barchetta ◽

Jeanette Arvastsson ◽

Luis Sarmiento ◽

Corrado M. Cilio

Keyword(s):

Dna Methylation ◽

Type 1 Diabetes ◽

Environmental Factors ◽

Autoimmune Diseases ◽

Epigenetic Mechanism ◽

Fetal Life ◽

Epigenetic Changes ◽

Maternal Factors ◽

Immune Mediated

Organ-specific autoimmune diseases, such as type 1 diabetes, are believed to result from T-cell-mediated damage of the target tissue. The immune-mediated tissue injury, in turn, is known to depend on complex interactions between genetic and environmental factors. Nevertheless, the mechanisms whereby environmental factors contribute to the pathogenesis of autoimmune diseases remain elusive and represent a major untapped target to develop novel strategies for disease prevention. Given the impact of the early environment on the developing immune system, epigenetic changes induced by maternal factors during fetal life have been linked to a likelihood of developing an autoimmune disease later in life. In humans, DNA methylation is the epigenetic mechanism most extensively investigated. This review provides an overview of the critical role of DNA methylation changes induced by prenatal maternal conditions contributing to the increased risk of immune-mediated diseases on the offspring, with a particular focus on T1D. A deeper understanding of epigenetic alterations induced by environmental stressors during fetal life may be pivotal for developing targeted prevention strategies of type 1 diabetes by modifying the maternal environment.

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Methyl donor micronutrients, CD40-ligand methylation and disease activity in systemic lupus erythematosus: A cross-sectional association study

Lupus ◽

10.1177/09612033211034559 ◽

2021 ◽

pp. 096120332110345

Author(s):

Stefan Vordenbäumen ◽

Alexander Sokolowski ◽

Anna Rosenbaum ◽

Claudia Gebhard ◽

Johanna Raithel ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Dna Methylation ◽

T Cells ◽

Disease Activity ◽

Lupus Erythematosus ◽

Cd40 Ligand ◽

Systemic Lupus ◽

Methyl Donors ◽

Methyl Donor ◽

The Mean

Objective Hypomethylation of CD40-ligand (CD40L) in T-cells is associated with increased disease activity in systemic lupus erythematosus (SLE). We therefore investigated possible associations of dietary methyl donors and products with CD40L methylation status in SLE. Methods Food frequency questionnaires were employed to calculate methyl donor micronutrients in 61 female SLE patients (age 45.7 ± 12.0 years, disease duration 16.2 ± 8.4 years) and compared to methylation levels of previously identified key DNA methylation sites (CpG17 and CpG22) within CD40L promotor of T-cells using quantitative DNA methylation analysis on the EpiTYPER mass spectrometry platform. Disease activity was assessed by SLE Disease Activity Index (SLEDAI). Linear regression modelling was used. P values were adjusted according to Benjamini & Hochberg. Results Amongst the micronutrients assessed (g per day), methionine and cysteine were associated with methylation of CpG17 (β = 5.0 (95%CI: 0.6-9.4), p = 0.04; and β = 2.4 (0.6-4.1), p = 0.02, respectively). Methionine, choline, and cysteine were additionally associated with the mean methylation of the entire CD40L (β = 9.5 (1.0-18.0), p = 0.04; β = 1.6 (0.4-3.0), p = 0.04; and β = 4.3 (0.9-7.7), p = 0.02, respectively). Associations of the SLEDAI with hypomethylation were confirmed for CpG17 (β=-32.6 (-60.6 to -4.6), p = 0.04) and CpG22 (β=-38.3 (-61.2 to -15.4), p = 0.004), but not the mean methylation of CD40L. Dietary products with the highest impact on methylation included meat, ice cream, white bread, and cooked potatoes. Conclusions Dietary methyl donors may influence DNA methylation levels and thereby disease activity in SLE.

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DNA methylome signatures of prenatal exposure to synthetic glucocorticoids in hippocampus and peripheral whole blood of female guinea pigs in early life

Translational Psychiatry ◽

10.1038/s41398-020-01186-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Aya Sasaki ◽

Margaret E. Eng ◽

Abigail H. Lee ◽

Alisa Kostaki ◽

Stephen G. Matthews

Keyword(s):

Dna Methylation ◽

Whole Blood ◽

Guinea Pigs ◽

Critical Role ◽

Methylation Status ◽

Peripheral Tissues ◽

Epigenetic Biomarkers ◽

Differentially Methylated Genes ◽

Increased Risk ◽

Synthetic Glucocorticoids

AbstractSynthetic glucocorticoids (sGC) are administered to women at risk of preterm delivery, approximately 10% of all pregnancies. In animal models, offspring exposed to elevated glucocorticoids, either by administration of sGC or endogenous glucocorticoids as a result of maternal stress, show increased risk of developing behavioral, endocrine, and metabolic dysregulation. DNA methylation may play a critical role in long-lasting programming of gene regulation underlying these phenotypes. However, peripheral tissues such as blood are often the only accessible source of DNA for epigenetic analyses in humans. Here, we examined the hypothesis that prenatal sGC administration alters DNA methylation signatures in guinea pig offspring hippocampus and whole blood. We compared these signatures across the two tissue types to assess epigenetic biomarkers of common molecular pathways affected by sGC exposure. Guinea pigs were treated with sGC or saline in late gestation. Genome-wide modifications of DNA methylation were analyzed at single nucleotide resolution using reduced representation bisulfite sequencing in juvenile female offspring. Results indicate that there are tissue-specific as well as common methylation signatures of prenatal sGC exposure. Over 90% of the common methylation signatures associated with sGC exposure showed the same directionality of change in methylation. Among differentially methylated genes, 134 were modified in both hippocampus and blood, of which 61 showed methylation changes at identical CpG sites. Gene pathway analyses indicated that prenatal sGC exposure alters the methylation status of gene clusters involved in brain development. These data indicate concordance across tissues of epigenetic programming in response to alterations in glucocorticoid signaling.

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Epigenetic Contribution and Genomic Imprinting Dlk1-Dio3 miRNAs in Systemic Lupus Erythematosus

Genes ◽

10.3390/genes12050680 ◽

2021 ◽

Vol 12 (5) ◽

pp. 680

Author(s):

Rujuan Dai ◽

Zhuang Wang ◽

S. Ansar Ahmed

Keyword(s):

Systemic Lupus Erythematosus ◽

Dna Methylation ◽

Lupus Erythematosus ◽

Critical Role ◽

Methylation Status ◽

Transcriptional Level ◽

Dna Hypomethylation ◽

Systemic Lupus ◽

Multiple Organs ◽

Genetic Imprinting

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease that afflicts multiple organs, especially kidneys and joints. In addition to genetic predisposition, it is now evident that DNA methylation and microRNAs (miRNAs), the two major epigenetic modifications, are critically involved in the pathogenesis of SLE. DNA methylation regulates promoter accessibility and gene expression at the transcriptional level by adding a methyl group to 5′ cytosine within a CpG dinucleotide. Extensive evidence now supports the importance of DNA hypomethylation in SLE etiology. miRNAs are small, non-protein coding RNAs that play a critical role in the regulation of genome expression. Various studies have identified the signature lupus-related miRNAs and their functional contribution to lupus incidence and progression. In this review, the mutual interaction between DNA methylation and miRNAs regulation in SLE is discussed. Some lupus-associated miRNAs regulate DNA methylation status by targeting the DNA methylation enzymes or methylation pathway-related proteins. On the other hand, DNA hyper- and hypo-methylation are linked with dysregulated miRNAs expression in lupus. Further, we specifically discuss the genetic imprinting Dlk1-Dio3 miRNAs that are subjected to DNA methylation regulation and are dysregulated in several autoimmune diseases, including SLE.

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Salivary DNA Methylation as an Epigenetic Biomarker for Head and Neck Cancer. Part I: A Diagnostic Accuracy Meta-Analysis

Journal of Personalized Medicine ◽

10.3390/jpm11060568 ◽

2021 ◽

Vol 11 (6) ◽

pp. 568

Author(s):

Óscar Rapado-González ◽

Cristina Martínez-Reglero ◽

Ángel Salgado-Barreira ◽

Laura Muinelo-Romay ◽

Juan Muinelo-Lorenzo ◽

...

Keyword(s):

Dna Methylation ◽

Head And Neck Cancer ◽

Diagnostic Accuracy ◽

Head And Neck ◽

Likelihood Ratio ◽

Neck Cancer ◽

Meta Analysis ◽

Positive Likelihood Ratio ◽

Epigenetic Mechanism ◽

Cochrane Library

DNA hypermethylation is an important epigenetic mechanism for gene expression inactivation in head and neck cancer (HNC). Saliva has emerged as a novel liquid biopsy representing a potential source of biomarkers. We performed a comprehensive meta-analysis to evaluate the overall diagnostic accuracy of salivary DNA methylation for detecting HNC. PubMed EMBASE, Web of Science, LILACS, and the Cochrane Library were searched. Study quality was assessed by the Quality Assessment for Studies of Diagnostic Accuracy-2, and sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (dOR), and their corresponding 95% confidence intervals (CIs) were calculated using a bivariate random-effect meta-analysis model. Meta-regression and subgroup analyses were performed to assess heterogeneity. Eighty-four study units from 18 articles with 8368 subjects were included. The pooled sensitivity and specificity of salivary DNA methylation were 0.39 and 0.87, respectively, while PLR and NLR were 3.68 and 0.63, respectively. The overall area under the curve (AUC) was 0.81 and the dOR was 8.34. The combination of methylated genes showed higher diagnostic accuracy (AUC, 0.92 and dOR, 36.97) than individual gene analysis (AUC, 0.77 and dOR, 6.02). These findings provide evidence regarding the potential clinical application of salivary DNA methylation for HNC diagnosis.

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Transcriptional coregualtor NUPR1 maintains tamoxifen resistance in breast cancer cells

Cell Death and Disease ◽

10.1038/s41419-021-03442-z ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Lingling Wang ◽

Jiashen Sun ◽

Yueyuan Yin ◽

Yanan Sun ◽

Jinyi Ma ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Critical Role ◽

Endocrine Resistance ◽

Autophagic Flux ◽

Physical Interaction ◽

Premature Senescence ◽

Breast Cancers ◽

Transcriptional Coregulator

AbstractTo support cellular homeostasis and mitigate chemotherapeutic stress, cancer cells must gain a series of adaptive intracellular processes. Here we identify that NUPR1, a tamoxifen (Tam)-induced transcriptional coregulator, is necessary for the maintenance of Tam resistance through physical interaction with ESR1 in breast cancers. Mechanistically, NUPR1 binds to the promoter regions of several genes involved in autophagy process and drug resistance such as BECN1, GREB1, RAB31, PGR, CYP1B1, and regulates their transcription. In Tam-resistant ESR1 breast cancer cells, NUPR1 depletion results in premature senescence in vitro and tumor suppression in vivo. Moreover, enforced-autophagic flux augments cytoplasmic vacuolization in NUPR1-depleted Tam resistant cells, which facilitates the transition from autophagic survival to premature senescence. Collectively, these findings suggest a critical role for NUPR1 as a transcriptional coregulator in enabling endocrine persistence of breast cancers, thus providing a vulnerable diagnostic and/or therapeutic target for endocrine resistance.

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Epigenome-wide associations between observed maternal sensitivity and offspring DNA methylation: a population-based prospective study in children

Psychological Medicine ◽

10.1017/s0033291720004353 ◽

2020 ◽

pp. 1-11

Author(s):

Lorenza Dall’ Aglio ◽

Jolien Rijlaarsdam ◽

Rosa H. Mulder ◽

Alexander Neumann ◽

Janine F. Felix ◽

...

Keyword(s):

Dna Methylation ◽

Stress Responses ◽

Association Studies ◽

Maternal Sensitivity ◽

Population Based ◽

Epigenetic Mechanism ◽

Developmental Problems ◽

Maternal Caregiving ◽

Typical Variation

Abstract Background Experimental work in animals has shown that DNA methylation (DNAm), an epigenetic mechanism regulating gene expression, is influenced by typical variation in maternal care. While emerging research in humans supports a similar association, studies to date have been limited to candidate gene and cross-sectional approaches, with a focus on extreme deviations in the caregiving environment. Methods Here, we explored the prospective association between typical variation in maternal sensitivity and offspring epigenome-wide DNAm, in a population-based cohort of children (N = 235). Maternal sensitivity was observed when children were 3- and 4-years-old. DNAm, quantified with the Infinium 450 K array, was extracted at age 6 (whole blood). The influence of methylation quantitative trait loci (mQTLs), DNAm at birth (cord blood), and confounders (socioeconomic status, maternal psychopathology) was considered in follow-up analyses. Results Genome-wide significant associations between maternal sensitivity and offspring DNAm were observed at 13 regions (p < 1.06 × 10−07), but not at single sites. Follow-up analyses indicated that associations at these regions were in part related to genetic factors, confounders, and baseline DNAm levels at birth, as evidenced by the presence of mQTLs at five regions and estimate attenuations. Robust associations with maternal sensitivity were found at four regions, annotated to ZBTB22, TAPBP, ZBTB12, and DOCK4. Conclusions These findings provide novel leads into the relationship between typical variation in maternal caregiving and offspring DNAm in humans, highlighting robust regions of associations, previously implicated in psychological and developmental problems, immune functioning, and stress responses.

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