s-adenosylhomocysteine and Neoplasms

Nutritional epigenetics has emerged as a novel mechanism underlying gene-diet interactions, further elucidating the modulatory role of nutrition in aging and age-related disease development. Epigenetics is defined as a heritable modification to the DNA that regulates chromosome architecture and modulates gene expression without changes in the underlying bp sequence, ultimately determining phenotype from genotype. DNA methylation and post-translational histone modifications are classical levels of epigenetic regulation. Epigenetic phenomena are critical from embryonic development through the aging process, with aberrations in epigenetic patterns emerging as aetiological mechanisms in many age-related diseases such as cancer, CVD and neurodegenerative disorders. Nutrients can act as the source of epigenetic modifications and can regulate the placement of these modifications. Nutrients involved in one-carbon metabolism, namely folate, vitamin B12, vitamin B6, riboflavin, methionine, choline and betaine, are involved in DNA methylation by regulating levels of the universal methyl donor S-adenosylmethionine and methyltransferase inhibitor S-adenosylhomocysteine. Other nutrients and bioactive food components such as retinoic acid, resveratrol, curcumin, sulforaphane and tea polyphenols can modulate epigenetic patterns by altering the levels of S-adenosylmethionine and S-adenosylhomocysteine or directing the enzymes that catalyse DNA methylation and histone modifications. Aging and age-related diseases are associated with profound changes in epigenetic patterns, though it is not yet known whether these changes are programmatic or stochastic in nature. Future work in this field seeks to characterise the epigenetic pattern of healthy aging to ultimately identify nutritional measures to achieve this pattern.

Topics: Aging; Animals; Cardiovascular Diseases; Diet; DNA Methylation; Epigenesis, Genetic; Epigenomics; Humans; Micronutrients; Neoplasms; Neurodegenerative Diseases; S-Adenosylhomocysteine; S-Adenosylmethionine

5'-Methylthioadenosine (MTA) is a naturally occurring sulfur-containing nucleoside present in all mammalian tissues. MTA is produced from S-adenosylmethionine mainly through the polyamine biosynthetic pathway, where it behaves as a powerful inhibitory product. This compound is metabolized solely by MTA-phosphorylase, to yield 5-methylthioribose-1-phosphate and adenine, a crucial step in the methionine and purine salvage pathways, respectively. Abundant evidence has accumulated over time suggesting that MTA can affect cellular processes in many ways. MTA has been shown to influence numerous critical responses of the cell including regulation of gene expression, proliferation, differentiation and apoptosis. Although most of these responses have been observed at the pharmacological level, their specificity makes it tempting to speculate that endogenous MTA could play a regulatory role in the cell. Finally, observations carried out in models of liver damage and cancer demonstrate a therapeutic potential for MTA that deserves further consideration.

Topics: Adenine; Animals; Apoptosis; Cell Differentiation; Deoxyadenosines; Gene Expression Regulation; Humans; Methionine; Neoplasms; Purines; S-Adenosylhomocysteine; Thionucleosides

Most biological processes, including diseases, involve genetic and non-genetic factors. Also, the realization of a genetic potential may depend on environmental factors by directly affecting the expression of gene(s). Exactly how different environmental factors affect gene expression is not well understood. One of the mechanisms may involve DNA methylation and thereby gene expression. Diet, chemicals, and metals are known to affect DNA methylation and other epigenetic processes but are just beginning to be elucidated. For example, methylation of cytosine(s) in the promoter region could prevent the binding of transcription factors or create binding sites for complexes that deacetylate neighboring histones that in turn compact the chromatin, encouraging a gene to become silent. This article will discuss DNA methylation as an epigenetic mechanism of gene regulation and examine how factors like diet, chemicals, and metals may affect DNA methylation. The effect of alterations in DNA methylation may include aberrant expression of genes or genomes and chromosomal instability, which in turn may contribute to the etiology of complex multifactorial diseases. A similar mechanism is now recognized in a number of cancers. There is also indirect evidence to suggest that methylation could apply to a number of complex diseases, including schizophrenia.

Topics: Diet; DNA Methylation; Female; Food-Drug Interactions; Gene Expression Regulation; Humans; Maternal Nutritional Physiological Phenomena; Neoplasms; Pregnancy; S-Adenosylhomocysteine; S-Adenosylmethionine; Schizophrenia

Topics: Adenosine; Animals; Azacitidine; Carcinogens; Cell Line; Cell Transformation, Neoplastic; Cell Transformation, Viral; Choline; DNA; DNA (Cytosine-5-)-Methyltransferases; DNA, Viral; Ethionine; Gene Expression Regulation; Homocysteine; Humans; Methionine; Methylation; Methyltransferases; Neoplasms; Oncogenes; Oncogenic Viruses; S-Adenosylhomocysteine; S-Adenosylmethionine; Simian virus 40

Selective manipulation of the epitranscriptome could be beneficial for the treatment of cancer and also broaden the understanding of epigenetic inheritance. Inhibitors of the tRNA methyltransferase DNMT2, the enzyme catalyzing the

Topics: Archaeal Proteins; Caco-2 Cells; DNA; Humans; Methyltransferases; Neoplasms; S-Adenosylhomocysteine; S-Adenosylmethionine

Topics: Animals; Binding Sites; Cell Line, Tumor; Drug Discovery; Drug Screening Assays, Antitumor; Hematopoietic Stem Cells; Humans; Leukemia, Myeloid, Acute; Mass Spectrometry; Methyltransferases; Mice; Models, Molecular; Molecular Targeted Therapy; Neoplasm Proteins; Neoplasms; Neoplastic Stem Cells; Protein Conformation; S-Adenosylhomocysteine; Xenograft Model Antitumor Assays

Cysteine acts both as a building unit for protein translation and as the limiting substrate for glutathione synthesis to support the cellular antioxidant system. In addition to transporter-mediated uptake, cellular cysteine can also be synthesized from methionine through the transsulfuration pathway. Here, we investigate the regulation of transsulfuration and its role in sustaining cell proliferation upon extracellular cysteine limitation, a condition reported to occur in human tumors as they grow in size. We observed constitutive expression of transsulfuration enzymes in a subset of cancer cell lines, while in other cells, these enzymes are induced following cysteine deprivation. We show that both constitutive and inducible transsulfuration activities contribute to the cellular cysteine pool and redox homeostasis. The rate of transsulfuration is determined by the cellular capacity to conduct methylation reactions that convert S-adenosylmethionine to S-adenosylhomocysteine. Finally, our results demonstrate that transsulfuration-mediated cysteine synthesis is critical in promoting tumor growth in vivo.

Topics: A549 Cells; Animals; Cell Proliferation; Cysteine; Extracellular Space; Female; Gene Knockout Techniques; Hep G2 Cells; Heterografts; Humans; Male; MCF-7 Cells; Methionine; Mice; Mice, Inbred NOD; Mice, Nude; Mice, SCID; Neoplasms; Protamines; S-Adenosylhomocysteine; S-Adenosylmethionine; Serine; Tumor Burden

Many different types of cancer cells have been shown to be methionine (MET) dependent. Cancer cells, unlike normal cells, grow poorly or not at all when MET is restricted. Cancer cells have an elevated requirement for exogenous MET for growth, despite high levels of endogenous synthesis. This requirement reflects increased utilization of MET by cancer cells, analogous to increased utilization glucose by cancer cells (Warburg effect). To answer the critical question of whether MET-dependent cancer cells synthesize normal amounts of MET, we determined the levels of MET, S-adenosylmethionine (AdoMET), and S-adenosylhomocysteine (AdoHCY) that were synthesized by MET-dependent cancer cells under conditions of MET restriction. We demonstrated that MET-dependent cells synthesize a normal amount of endogenously synthesized MET but are still deficient in AdoMET. In contrast, exogenously supplied MET results in normal AdoMET levels. The ratio of AdoMET to AdoHCY is low in MET-dependent cells growing in MET-restricted medium but is normal when MET is supplied. Under conditions of MET restriction, the low AdoMET/AdoHCY ratio probably limits proliferation of MET-dependent cancer cells. The amount of free MET is also low in MET-dependent cancer cells under MET restriction. The elevated MET requirement for cancer cells may be due to enhanced overall rates of transmethylation compared to normal human cells. Thus, MET-dependent cancer cells have low levels of free MET, low levels of AdoMET, and elevated levels of AdoHCY under conditions of MET restriction probably due to overuse of MET for transmethylation reactions ("Hoffman effect"), thereby blocking cellular proliferation.

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Cell Line, Tumor; Cell Proliferation; Chromatography, High Pressure Liquid; Homocysteine; Humans; Methionine; Methylation; Neoplasms; S-Adenosylhomocysteine; S-Adenosylmethionine

Polycomb repressive complex 2 (PRC2) catalyzes histone H3K27 trimethylation (H3K27me3), a hallmark of gene silencing. Here we report the crystal structures of an active PRC2 complex of 170 kilodaltons from the yeast Chaetomium thermophilum in both basal and stimulated states, which contain Ezh2, Eed, and the VEFS domain of Suz12 and are bound to a cancer-associated inhibiting H3K27M peptide and a S-adenosyl-l-homocysteine cofactor. The stimulated complex also contains an additional stimulating H3K27me3 peptide. Eed is engulfed by a belt-like structure of Ezh2, and Suz12(VEFS) contacts both of these two subunits to confer an unusual split active SET domain for catalysis. Comparison of PRC2 in the basal and stimulated states reveals a mobile Ezh2 motif that responds to stimulation to allosterically regulate the active site.

Topics: Allosteric Regulation; Amino Acid Sequence; Catalysis; Catalytic Domain; Chaetomium; Crystallography, X-Ray; Fungal Proteins; Gene Silencing; Histones; Humans; Jumonji Domain-Containing Histone Demethylases; Methylation; Molecular Sequence Data; Mutation; Neoplasms; Polycomb Repressive Complex 2; Protein Structure, Tertiary; S-Adenosylhomocysteine; Transcription, Genetic

Several epidemiological studies have suggested a modulatory effect of dietary folate intake on the risk of colorectal cancer. The molecular basis for this inverse association is not clearly understood, but may involve alterations in DNA methylation. In this study, we examined the levels of methylation intermediates [S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH)] and of global DNA methylation in the pre-neoplastic small intestine of Min (multiple intestinal neoplasia) mice. We also studied the effect of folate/choline deficiency on these parameters and on tumor multiplicity in this animal model. In folate-adequate Min mice, we identified positive linear correlations between SAM or SAH and tumor numbers (R(2) = 0.38, P < 0.005; R(2) = 0.26, P = 0.025, respectively). A positive correlation between global DNA hypomethylation and tumor multiplicity was also observed (R(2) = 0.29, P = 0.014). These three biochemical determinants (SAM, SAH and DNA hypomethylation) may, therefore, serve as early markers of cell transformation. Folate/choline deficiency, however, did not produce a consistent effect on tumor numbers in three separate experiments. As an increase in tumor numbers was observed only in folate- and choline-deficient mice with low levels of SAM and DNA hypomethylation, the modulatory role of folate may be dependent on the transformation state of the cell.

Topics: Animals; Biomarkers; Choline Deficiency; Diet; DNA Methylation; Folic Acid Deficiency; Intestinal Neoplasms; Methionine; Mice; Neoplasms; Precancerous Conditions; S-Adenosylhomocysteine; S-Adenosylmethionine

An increasing number of both clinical and experimental studies have shown an association between deficiencies of the dietary sources of physiological methyl groups and cancer formation. The critical metabolic intermediate in a determination of methylation status is S-adenosylmethionine (SAM), the body's chief physiological methyl donor. The present study examined the erythrocyte levels of SAM and of its demethylated metabolite S-adenosylhomocysteine (SAH) in 66 normal subjects (33 men and 33 women), whose blood had been drawn at days 0, 7 and 14 of an experimental period during which they were fed a fixed diet. The plasma levels of homocysteine (HCys) were also determined in the same individuals at the same time points. In addition, the subjects had completed a food frequency questionnaire (FFQ) describing their usual dietary habits before being placed on the dietary regimen. The blood levels of SAM, SAH, and HCys were compared with the dietary intakes of folate, vitamin B(6), fats, and calories, both prior to using the FFQ and during the experimental period. The results indicated that the intraindividual differences were very low, but the interindividual differences were large for the values of SAM, SAH, SAM:SAH ratios, and HCys. Interestingly, the blood levels of SAM and HCys were higher in men than in women and generally showed the expected correlations with folate intake i.e., positive for SAM and negative for HCys. The intakes of folate (276 microg/days) and B(6) (1.87 mg/days) during the 2-week experimental period were relatively low compared with the usual intakes of these vitamins (375 and 2.06 mg/day for folate and B(6), respectively) but correlated well with each other during both periods of the study. Surprisingly, both men and women showed a significant rise in erythrocyte SAM:SAH ratios as a function of age. In addition, the combined results from men and women, even adjusted for gender, showed significant correlations between HCys and both weight and body mass index. On the other hand, during the experimental period of the study, blood SAM levels were inversely correlated with the intakes of both fat and calories when the data for both men and women were combined and adjusted for gender. The blood determinations of SAM and related compounds showed a high degree of reproducibility over time and thus appear to provide a practical marker of methylation status for the assessment of cancer risk from dietary, environmental, and genetic factors.

Topics: Body Mass Index; Diet; Dietary Fats; Erythrocytes; Female; Folic Acid; Homocysteine; Humans; Male; Neoplasms; Pyridoxine; Reference Values; Risk Factors; S-Adenosylhomocysteine; S-Adenosylmethionine

Sites of cytosine methylation are known to be hot spots for C.G to T.A mutations in a number of systems, including human cells. Traditionally, spontaneous hydrolytic deamination of 5-methylcytosine to thymine has been invoked as the cause of this phenomenon. We show here that a bacterial cytosine methyltransferase can convert 5-methylcytosine in DNA to thymine and that this reaction creates a mutational hot spot at a site of DNA methylation. The reaction is fairly insensitive to the methyl donor in the reaction, S-adenosylmethionine. In many cancers, the most frequent class of mutations is C to T changes within CG dinucleotides of the tumor suppressor gene p53. Because of the similarities of the reaction mechanisms of mammalian and bacterial enzymes and the physiology of the cancer cells, this reaction is expected to contribute to mutations at CG dinucleotides in precancerous cells.

Topics: 5-Methylcytosine; Cytosine; DNA; DNA-Cytosine Methylases; Escherichia coli; Humans; Methylation; Molecular Structure; Mutagenesis; Neoplasms; S-Adenosylhomocysteine; S-Adenosylmethionine; Thymine

Methionine dependence is a metabolic defect found thus far only in transformed and malignant cells. The defect is manifested as the inability of cells to grow in media in which methionine (Met) is replaced by its immediate precursor homocysteine (Hcy). We have termed this Met- Hcy+ media. We demonstrate here that methionine-dependent cells derived from human tumors, compared to normal methionine-independent cells, have low levels of free Met, low levels of S-adenosylmethionine (AdoMet) and elevated levels of S-adenosylhomocysteine (AdoHcy) when incubated in Met- Hcy+ medium. Methionine-independent human tumor cells also have very low levels of free Met compared to normal cells but generally have levels of AdoMet and AdoHcy comparable to normal cells in Met- Hcy+ medium. All tumor cell types incorporate amounts of Met into protein similar to normal methionine-independent human fibroblasts when incubated in Met- Hcy+ medium, thereby indicating apparently normal levels of Met synthesis in the tumor cells. The methionine-independent tumor cell lines in Met- Hcy+ medium seem able to regulate their AdoMet/AdoHcy ratios normally despite this defect in having very low levels of free Met. Thus, in a diverse set of human tumor cell lines, all are defective in at least one aspect of Met metabolism, giving rise to the possibility of a general metabolic defect in cancer.

Topics: Cell Line; Homocysteine; Humans; Methionine; Models, Biological; Neoplasms; S-Adenosylhomocysteine; S-Adenosylmethionine