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PubMed2000

Genetic and epigenetic alterations in carcinogenesis.

Precise and deliberate observations on tumors stand true for decades, and then meet mechanistic explanations. The presence of genetic alterations in tumors is now widely accepted, and explains the irreversible nature of tumors. However, observations on tissue differentiation indicated that it shares something in common with carcinogenesis, that is, "epigenetic" changes. Now, DNA methylation in CpG sites is known to be precisely regulated in tissue differentiation, and is supposed to be playing key roles. Many tumor suppressor genes are known to be inactivated by the hypermethylation of their promoter regions. DNA methylation is connected to histone deacetylation and chromatin structure, and regulatory enzymes of DNA methylation are being cloned. Dedifferentiation, dis(dys)differentiation and convergence of cancer cells were studied phenotypically and biochemically, and are now explained from molecular aspects of disturbances in tissue-specific transcription factors. Spontaneous regression of malignant tumors enchanted researchers, and it is now noticed that genes inactivated by hypermethylation are frequently involved in tumors that relatively often undergo spontaneous regression. Carcinogenic mechanisms of some carcinogens seem to involve modifications of epigenetic switch, and some dietary factors also have the possibility to modify the switches. Based on the growing understanding of the roles of DNA methylation, several new methodologies were developed to make a genome-wide search for changes in DNA methylation. Now, a wave of new findings is in sight.

DNA Methylation↗
PubMed1997

Mutagenic and epigenetic effects of DNA methylation.

Tumorigenesis begins with the disregulated growth of an abnormal cell that has acquired the ability to divide more rapidly than its normal counterparts (Nowell, P.C. (1976) Science, 194, 23-28 [1]). Alterations in global levels and regional changes in the patterns of DNA methylation are among the earliest and most frequent events known to occur in human cancers (Feinberg and Vogelstein (1983) Nature, 301, 89-92 ([2]); Gama-Sosa, M.A. et al. (1983) Nucleic Acids Res., 11, 6883-6894 ([3]); Jones, P.A. (1986) Cancer Res., 46, 461-466 [4]). These changes in methylation may impair the proper expression and/or function of cell-cycle regulatory genes and thus confer a selective growth advantage to affected cells. Developments in the field of cancer research over the past few years have led to an increased understanding of the role DNA methylation may play in tumorigenesis. Many of these studies have investigated two major mechanisms by which DNA methylation may lead to aberrant cell cycle control: (1) through the generation of transition mutations via deamination-driven events resulting in the inactivation of tumor suppressor genes, or (2) by altering levels of gene expression through epigenetic effects at CpG islands. The mechanisms by which the normal function of growth regulatory genes may become affected by the mutagenic and epigenetic properties of DNA methylation will be discussed in the framework of recent discoveries in the field.

5-Methylcytosine↗
PubMed1997

DNA methylation, heterochromatin and epigenetic carcinogens.

This paper will explore emerging concepts related to alternative carcinogenic mechanisms of 'non-mutagenic,' and hence epigenetic, carcinogens that may heritably alter DNA methylation without changing the underlying DNA sequence. In this review, we will touch on the basic concepts of DNA methylation, and will elaborate in greater detail on related topics including chromatin condensation, and heterochromatin spreading that is well known to induce gene silencing by position effect variegation in Drosophila and other species. Data from our model transgenic G12 cell system will be presented to support our hypothesis that certain carcinogens, such as nickel, may be carcinogenic not primarily because of their overt mutability, but rather as the result of their ability to promote DNA hypermethylation of important cancer-related genes. We will conclude with a discussion of the broader relevance of our findings and its application to other so-called 'epigenetic' carcinogens.

Animals↗
PubMed2005

Human embryonic stem cell methyl cycle enzyme expression: modelling epigenetic programming in assisted reproduction?

To investigate a possible mechanism for inducing epigenetic defects in the preimplantation embryo, a human embryonic stem cell model was developed, and gene expression of the key methyl cycle enzymes, MAT2A, MAT2B, GNMT, SAHH, CBS, CGL, MTR, MTRR, BHMT, BHMT2, mSHMT, cSHMT and MTHFR was demonstrated, while MAT1 was barely detectable. Several potential acceptors of cycle-generated methyl groups, the DNA methyltransferases (DNMT1, DNMT3A, DNMT3B and DNMT3L), glycine methyltransferase and the polyamine biosynthetic enzymes, SAM decarboxylase and ornithine decarboxylase, were also expressed. Expression of folate receptor alpha suggests a propensity for folate metabolism. Methotrexate-induced depletion of folate resulted in elevated intracellular homocysteine concentration after 7 days in culture and a concomitant increase in cysteine and glutathione, indicating clearance of homocysteine through the transulphuration pathway. These studies indicate that altered methyl group metabolism provides a potential mechanism for inducing epigenetic changes in the preimplantation embryo.

Cell Proliferation↗
PubMed2003

Epigenetic reprogramming in early embryonic development: effects of in-vitro production and somatic nuclear transfer.

A considerable proportion of offspring, in particular in ruminants and mice, born from nuclear transfer (NT)-derived and in-vitro-produced (IVP) embryos is affected by multiple abnormalities of which a high birthweight and an extended gestation length are the predominant features; a phenomenon that has been called 'large offspring syndrome' (LOS). The underlying mechanisms are largely unknown at present, but alterations of epigenetic modifications of embryonic and fetal gene expression patterns, primarily caused by alterations in DNA methylation are thought to be involved in this syndrome. In mammals, DNA methylation is essential for the regulation of transcription during development and differentiation. This review summarizes results from studies in which mRNA expression patterns from IVP and NT-derived embryos were compared with those of their in-vivo counterparts. Numerous aberrations have been found ranging from suppression of expression to de-novo overexpression or more frequently to a significant up- or down-regulation of a specific gene. These observations emphasize the need for further epigenetic studies during preimplantation embryo development to gain insight into the molecular regulation correlated with an undisturbed embryonic and fetal development. Understanding molecular mechanisms will aid improvements in biotechnologies applied to early embryos in all species, including humans.

Animals↗
PubMedDate not supplied

Human pancreatic carcinoma cells activate maspin expression through loss of epigenetic control.

The maspin gene is not expressed in normal human pancreas, but its expression is acquired during human pancreatic carcinogenesis. In other normal human cells and their malignant counterparts, maspin expression is controlled through the epigenetic state of its promoter. In studies presented herein, we used bisulfite genomic sequencing and chromatin immunoprecipitation studies to show that maspin-negative pancreas cells have a methylated maspin promoter, and that the associated H3 and H4 histones are hypoacetylated. In contrast to normal pancreas, four of six human pancreatic carcinoma cell lines investigated displayed activation of maspin expression. This activation of maspin expression in pancreatic carcinoma cells was linked to demethylated promoters and hyperacetylation of the associated H3 and H4 histones. In addition, 5-aza-2'-deoxycytidine treatments activated maspin expression in the two maspin-negative pancreatic carcinoma cell lines, suggesting a causal role for cytosine methylation in the maintenance of a transcriptionally silent maspin gene. Thus, human pancreatic carcinoma cells acquire maspin expression through epigenetic derepression of the maspin locus, and in so doing appear to co-opt a normal cellular mechanism for the regulation of this gene.

Azacitidine↗
PubMed2002

Pharmacologic unmasking of epigenetically silenced tumor suppressor genes in esophageal squamous cell carcinoma.

We performed a comprehensive survey of commonly inactivated tumor suppressor genes in esophageal squamous cell carcinoma (ESCC) based on functional reactivation of epigenetically silenced tumor suppressor genes by 5-aza-2'-deoxycytidine and trichostatin A using microarrays containing 12599 genes. Among 58 genes identified by this approach, 44 (76%) harbored dense CpG islands in the promoter regions. Thirteen of twenty-two tested gene promoters were methylated in cell lines, and ten in primary ESCC accompanied by silencing at the mRNA level. Potent growth suppressive activity of three genes including CRIP-1, Apolipoprotein D, and Neuromedin U in ESCC cells was demonstrated by colony focus assays. Pharmacologic reversal of epigenetic silencing is a powerful approach for comprehensive identification of tumor suppressor genes in human cancers.

Azacitidine↗
PubMed2003

Epigenetic toxicity of hydroxylated biphenyls and hydroxylated polychlorinated biphenyls on normal rat liver epithelial cells.

2-Biphenylol, 3-biphenylol, 2,2'-biphenyldiol, 3,3'-biphenyldiol, 3-chloro-2-biphenylol, and 4,4'-dichloro-3-biphenylol were evaluated using the scrape-loading/dye transfer (SL/ DT) technique to determine in vitro gap junctional intercellular communication (GJIC) in a normal rat liver epithelial cell line as a measure of the epigenetic toxicity. Cytotoxicity was determined using the neutral red uptake assay. A dose range of 0-300 microM was examined. Only 3,3'-biphenyldiol and 4,4'-dichloro-3-biphenylol induced cytotoxicity within the tested dose ranges. Noncytotoxic doses were selected for evaluation of epigenetic toxicity. 4,4'-Dichloro-3-biphenylol was most inhibitory to GJIC at the lowest dose. The cytotoxicity and GJIC inhibitory effects observed for 4,4'-dichloro-3-biphenylol might be, although not exclusively, a consequence of the lipophilic nature of this chemical. 3-Chloro-2-biphenylol was least inhibitory to GJIC. 3-Chloro-2-biphenylol was less inhibitory to GJIC than 2-biphenylol because of the presence of the chlorine functional group, which appears to attenuate the toxic effect of the ortho-hydroxyl group. Although cells were capable of complete recovery of GJIC after removal of each of the chemicals, only with 2,2'-biphenyldiol and 4,4,'-dichloro-3-biphenylol did the cells demonstrate partial recovery without removal of the chemical. The more noncoplanar conformation of 2,2'-biphenyldiol and 2-biphenylol might explain their more inhibitory behavior in comparison to 3,3'-biphenyldiol and 3-biphenylol, respectively.

Animals↗
PubMed1998

Rapid tamoxifen-induced inactivation of an estrogenic response is accompanied by a localized epigenetic modification but not by mutations.

In a previous study (Cancer Res 54: 5860-5866, 1994), we observed irreversible inactivation of a chimeric estrogenic response induced by the antiestrogen 4-hydroxytamoxifen. This rapidly occurring effect (t1/2= 7 days) was not a consequence of a cell selection process, nor of a loss of estrogen receptor functionality, but was a direct antiestrogen effect occurring on every cell at the transcriptional level. In the present study, we analyzed the detailed methylation status of the chimeric gene, and investigated the gene for the presence of mutations. The inactivation process was found to be strictly correlated with a modification at a methylation-sensitive restriction site Not I borne by the integrated gene. As the gene promoter contains part of the Herpes simplex virus promoter for thymidine kinase. which is a CpG-rich promoter, we investigated the CpGs located in this part of the promoter by genomic sequencing procedures. None of these CpGs were methylated, suggesting that the inactivation process was not driven by particular modifications of this foreign part of the promoter. Furthermore, no mutations were found in the entire gene promoter of inactivated cells. In conclusion, the present study highlighted a connection between the rapid silencing of an estrogenic response induced by 4-hydroxytamoxifen, and a localized epigenetic modification of the corresponding gene. No genotoxicity of 4-hydroxytamoxifen was observed. Similar epigenetic modifications might also occur for natural genes, and lead to the acquisition of a new cell phenotype.

Breast Neoplasms↗
PubMed2000

Transgene silencing by the host genome defense: implications for the evolution of epigenetic control mechanisms in plants and vertebrates.

Increasing evidence supports the idea that various transgene silencing phenomena reflect the activity of diverse host defense responses that act ordinarily on natural foreign or parasitic sequences such as transposable elements, viroids, RNA and DNA viruses, and bacterial DNA. Transgenes or their transcripts can resemble these cellular invaders in a number of ways, thus making them targets of host protective reactions. At least two distinct host defense systems operate to silence transgenes. One acts at the genome level and is associated with de novo DNA methylation. A second line of defense operates post-transcriptionally and involves sequence-specific RNA degradation in the cytoplasm. Transgenes that are silenced as a consequence of the genome defense are revealing that de novo methylation can be cued by DNA-DNA or RNA-DNA interactions. These methylation signals can be interpreted in the context of transposable elements or their transcripts. During evolution, as transposable elements accumulated in plant and vertebrate genomes and as they invaded flanking regions of genes, the genome defense was possibly recruited to establish global epigenetic mechanisms to regulate gene expression. Transposons integrated into promoters of host genes could conceivably change expression patterns and attract methylation, thus imposing on endogenous genes the type of epigenetic regulation associated with the genome defense. This recruitment process might have been particularly effective in the polyploid genomes of plants and early vertebrates. Duplication of the entire genome in polyploids buffers against insertional mutagenesis by transposable elements and permits their infiltration into individual copies of duplicated genes.

Animals↗
PubMed2003

Epigenetic interactions between Arabidopsis transgenes: characterization in light of transgene integration sites.

The stochastic variability of expression that is a characteristic of eukaryotic nuclear transgenes is often attributed to epigenetic mechanisms that are triggered by repetitive transgene locus structures and influenced by chromosomal position effects. In order to address the contribution of chromosomal position effects in the context of a fully sequenced genome, a novel set of transgene loci was established in the compact genome of Arabidopsis thaliana. Transgenes expressing GFP-tagged or GUS-tagged fusion proteins of Arabidopsis COP1 collectively displayed three types of gene silencing, which are distinguished by their developmental timing, gene dosage dependence, (post)transcriptional control, and extent of endogene co-suppression. Subsequently, the heritability of epistatic interactions between allelic and non-allelic transgene loci was investigated in light of both intrinsic transgene features, in particular T-DNA copy number per locus, and chromosomal insertion sites. The notion that chromosomal flanking sequences underlie the ability of transgenes to function as masters or targets of epigenetically heritable trans-silencing interactions was generally not favored by our data. Moreover, among single T-DNA loci at different chromosomal locations the great majority showed homozygosity-dependent posttranscriptional silencing. However, spontaneous silencing (in cis) may be promoted by a pericentromeric location. Instead, intrinsic transgene features correlated with all major aspects of silencing behavior tested.

Arabidopsis↗
PubMed2004

Genetic and epigenetic changes in mammary epithelial cells may mimic early events in carcinogenesis.

Studies of human mammary epithelial cells from healthy individuals are providing novel insights into how early epigenetic and genetic events affect genomic integrity and fuel carcinogenesis. Key epigenetic changes, such as the hypermethylation of the p16 (INK4a) promoter sequences, create a previously unappreciated preclonal phase of tumorigenesis in which a subpopulation of mammary epithelial cells are positioned for progression to malignancy (Romanov et al. , 2001, Nature , 409:633-637; Tlsty et al. , 2001, J. Mammary Gland Biol. Neoplasia , 6:235-243). These key changes precede the clonal outgrowth of premalignant lesions and occur frequently in healthy, disease-free women. Understanding more about these early events should provide novel molecular candidates for prevention and therapy of breast cancer that target the process instead of the consequences of genomic instability. This review will highlight some of the key alterations that have been studied in human mammary epithelial cells in culture and relate them to events observed in vivo and discussed in accompanying reviews in this volume.

Breast Neoplasms↗
PubMed2000

PCNA connects DNA replication to epigenetic inheritance in yeast.

Formation of a heterochromatin-like structure results in transcriptional silencing at the HM mating-type loci and telomeres in Saccharomyces cerevisiae. Once formed, such epigenetically determined structures are inherited for many mitotic divisions. Here we show that mutations in the proliferating cell nuclear antigen (PCNA), an essential component at the DNA replication fork, reduced repression of genes near a telomere and at the silent mating-typelocus, HMR. The pol30-8 mutant displayed coexistence of both repressed (pink) and de-repressed (white) cells within a single colony when assayed with the ADE2 gene inserted at HMR. Unlike pol30-8, the pol30-6 and pol30-79 mutants partially reduced gene silencing at telomeres and the HMR and synergistically decreased silencing in cells lacking chromatin assembly factor 1 (CAF-1). All silencing defective mutants showed reduced binding to CAF-1 in vitro and altered chromatin association of the CAF-1 large subunit in vivo. Thus, PCNA participates in inheritance of both DNA and epigenetic chromatin structures during the S phase of the cell cycle, the latter by at least two mechanisms.

Carboxy-Lyases↗
PubMed1999

Cancer epigenetics comes of age.

The discovery of numerous hypermethylated promoters of tumour-suppressor genes, along with a better understanding of gene-silencing mechanisms, has moved DNA methylation from obscurity to recognition as an alternative mechanism of tumour-suppressor inactivation in cancer. Epigenetic events can also facilitate genetic damage, as illustrated by the increased mutagenicity of 5-methylcytosine and the silencing of the MLH1 mismatch repair gene by DNA methylation in colorectal tumours. We review here current mechanistic understanding of the role of DNA methylation in malignant transformation, and suggest Knudson's two-hit hypothesis should now be expanded to include epigenetic mechanisms of gene inactivation.

Animals↗
PubMed2001

Epigenetic change in IGF2R is associated with fetal overgrowth after sheep embryo culture.

Manipulation or non-physiological embryo culture environments can lead to defective fetal programming in livestock. Our demonstration of reduced fetal methylation and expression of ovine IGF2R suggests pre-implantation embryo procedures may be vulnerable to epigenetic alterations in imprinted genes. This highlights the potential benefits of epigenetic diagnostic screening in developing embryo procedures.

Abnormalities, Multiple↗
PubMed2001

Retrotransposons as epigenetic mediators of phenotypic variation in mammals.

Phenotypic variation in mammals is frequently attributed to the action of quantitative trait loci (QTL) or the environment, but may also be epigenetic in origin. Here we consider a mechanism for phenotypic variation based on interference of transcription by somatically active retrotransposons. Transcriptionally competent retrotransposons may number in the tens of thousands in mammalian genomes. We propose that silencing of retrotransposons occurs by cosuppression during early embryogenesis, but that this process is imperfect and produces a mosaic pattern of retrotransposon expression in somatic cells. Transcriptional interference by active retrotransposons perturbs expression of neighboring genes in somatic cells, in a mosaic pattern corresponding to activity of each retrotransposon. The epigenotype of retrotransposon activity is reset in each generation, but incomplete resetting can lead to heritable epigenetic effects. The stochastic nature of retrotransposon activity, and the very large number of genes that may be affected, produce subtle phenotypic variations even between genetically identical individuals, which may affect disease risk and be heritable in a non-mendelian fashion.

Animals↗
PubMed2001

The role of epigenetic modifications in retinoic acid receptor beta2 gene expression in human prostate cancers.

The retinoic acid receptor (RAR) beta gene is a putative tumor suppressor gene on chromosome 3p24, where a high incidence of loss of heterozygosity is detected in many types of tumors. Retinoic acid suppresses cancer cell growth through binding to RARs, especially RARbeta, indicating a critical role in mediating anticancer effects. Selective loss or down-regulation of RARbeta mRNA and protein has been reported in prostate cancers (PCas), although the mechanisms remain unclear. We investigated the role of epigenetic modification in RARbeta2 gene silencing. Aberrant methylation was detected in 11 of 14 (79%) primary PCas, 9 of 10 (90%) hormone-refractory PCas, and 2 of 4 (50%) PCa cell lines, but not in any normal prostate samples. Chromatin immunoprecipitation assay showed that all RARbeta2-negative cells (LNCaP, PC3, and DU145) were hypoacetylated at both histones H3 and H4. After exposure to 5-aza-2prime;-deoxycytidine treatment, Trichostatin A and all-trans retinoic acid induced partial demethylation, increased accumulation of acetylated histones, and markedly restored the expression of RARbeta2 in RARbeta2-negative cells. These data suggest that the RARbeta2 gene may be one of the frequently silenced genes by epigenetic modifications in PCa.

Base Sequence↗
PubMed2005

Epigenetic alterations in neuroendocrine tumors: methylation of RAS-association domain family 1, isoform A and p16 genes are associated with metastasis.

Well-differentiated neuroendocrine tumors including pancreatic endocrine tumors and carcinoid tumors are uncommon neoplasms that have site-specific differences in clinicopathological features, clinical course and genetic alterations. The epigenetic alterations in these tumors are not well characterized. We therefore compared methylation of the RAS-association domain family 1, isoform A (RASSF1A), p14, p16 and O6-methyl-guanine methyltransferase genes in neuroendocrine tumors from 47 patients including 16 pancreatic, 15 nonileal and 16 ileal neuroendocrine tumors. Methylation of the RASSF1A gene was present in 57% of tumors, p14 in 49%, p16 in 26% and O6-methyl-guanine methyltransferase in 13% of tumors. Ileal neuroendocrine tumors lacked methylation of O6-methyl-guanine methyltransferase gene (P = 0.04). RASSF1A methylation was associated with histopathologic type of tumors (P = 0.03) and lymph node metastasis (P = 0.004), and p16 methylation with older patient age (P = 0.002) and liver metastasis (P = 0.04). Two or more genes were methylated in 53% of tumors, one gene was methylated in 30% of tumors, and all four genes were unmethylated in 17% of tumors. Methylation of one or more gene was associated with older age of patients (P = 0.01), and methylation of two or more genes was associated with liver metastasis (P = 0.044). Our study shows that in neuroendocrine tumors epigenetic alterations vary by tumor subsite and clinicopathologic features, including age of onset, histopathologic type and metastasis status.

Aged↗