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At least 199 records · Page 11Linked to original sources

PubMed2006

Genetic and epigenetic biomarkers in cancer : improving diagnosis, risk assessment, and disease stratification.

Gene expression patterns change during the initiation, progression, and development of cancer, as a result of both genetic and epigenetic mechanisms. Genetic changes arise due to irreversible changes in the nucleotide sequence, whereas epigenetic changes occur due to changes in chromatin conformation, histone acetylation, and methylation of the CpG islands located primarily in the promoter region of a gene. Both genetic and epigenetic markers can potentially be utilized to identify different stages of tumor development. Several such markers exhibit high sensitivity and specificity for different tumor types and can be assayed in biofluids and other specimens collected by noninvasive technologies. In spite of the availability of large numbers of diagnostic markers, only a few have been clinically validated so far. The current status and the challenges in the field of genetic and epigenetic markers in cancer diagnosis, risk assessment, and disease stratification are discussed.

Biomarkers, Tumor↗

PubMed2006

Epigenetic mechanisms: a common theme in vertebrate and invertebrate memory formation.

In this review we address the idea that conservation of epigenetic mechanisms for information storage represents a unifying model in biology, with epigenetic mechanisms being utilized for cellular memory at levels from behavioral memory to development to cellular differentiation. Epigenetic mechanisms typically involve alterations in chromatin structure, which in turn regulate gene expression. An emerging idea is that the regulation of chromatin structure through histone acetylation and DNA methylation may mediate long-lasting behavioral change in the context of learning and memory. We find this idea fascinating because similar mechanisms are used for triggering and storing long-term 'memory' at the cellular level, for example when cells differentiate. An additional intriguing aspect of the hypothesis of a role for epigenetic mechanisms in information storage is that lifelong behavioral memory storage may involve lasting changes in the physical, three-dimensional structure of DNA itself.

Animals↗

PubMed2005

Epigenetic changes and repositioning determine the evolutionary fate of duplicated genes.

Consideration of epigenetic silencing, perhaps by DNA methylation, led to an epigenetic complementation (EC) model for evolution by gene duplication (Rodin and Riggs (2003) J. Mol. Evol., 56, 718-729). This and subsequent work on genome-wide analyses of gene duplicates in several eukaryotic species pointed to a fundamental link between localization in the genome, epigenetic regulation of expression, and the evolutionary fate of new redundant gene copies, which can be either non- or neo-functionalization. Our main message in this report is that repositioning of a new duplicate to an ectopic site epigenetically alters its expression pattern, and concomitantly the rate and direction of mutations. Furthermore, comparison of syntenic vs. non-syntenic pairs of gene duplicates of different age unambiguously indicates that repositioning saves redundant gene duplicates from pseudogenization and hastens their evolution towards a new development-time and tissue-specific pattern of function.

Animals↗

PubMed2004

Epigenetic gene silencing in acute promyelocytic leukemia.

The recent explosion in our knowledge of how chromatin organization modulates gene transcription has highlighted the importance of epigenetic mechanisms in the initiation and progression of human cancer. These epigenetic changes--in particular, aberrant promoter hypermethylation that is associated with inappropriate gene silencing--affect virtually every step in tumor progression. Intriguingly, methylation patterns are severely altered in tumors, with an overall hypomethylation of the genome and hypermethylation of islands of CpGs clusters within specific DNA regions. Though overexpression of DNA methyltransferases (DNMTs) has been proposed to be a mechanism for aberrant genome methylation, it does not explain the specific regional hypermethylation in cancer cells. We have analyzed the role of chromatin modifying activities in cell transformation using acute promyelocytic leukemia as a model system. This disease is caused by expression of the PML-RARalpha fusion protein, thus offering the opportunity of studying the mechanisms of leukemogenesis through molecular investigation of the activity of the directly transforming protein. Recent evidence suggests that PML-RARalpha as well as other leukemia-associated fusion proteins induce changes in the chromatin structure. Specifically, aberrant recruitment of different chromatin modifying enzymes to specific promoters induces DNA hypermethylation and heterochromatin formation, which consequentially leads to the transcriptional silencing of that genes. Importantly, these epigenetic modifications were found to contribute to the leukemogenic potential of PML-RARalpha. These observations suggest that epigenetic alterations could actively contribute to the development of APL and other hyperproliferative diseases.

Animals↗

PubMed2006

Lytic induction and apoptosis of Epstein-Barr virus-associated gastric cancer cell line with epigenetic modifiers and ganciclovir.

Epstein-Barr virus (EBV) is an oncogenic herpes virus. EBV gene transcription is regulated by an epigenetic mechanism to establish a persistent infection and to evade the host immune system. We found that low concentrations of epigenetic modifying agents, 5-aza-2'-deoxycytidine (5-aza-CdR) or trichostatin A (TSA), induced the expression of BMRF1, BZLF1, and BRLF1 genes, which are found in the lytic form of the virus, in an EBV-positive gastric cancer cell line. This effect did not involve PI3 kinase, MAP/ERK kinase, protein kinase C delta, or p38 MAPK signaling pathway. The cytotoxic effect of ganciclovir (GCV) was enhanced after the lytic induction by epigenetic modifiers, and the combination of GCV and epigenetic modifiers induced apoptosis, which is dependent on caspases. In conclusion, the combination of GCV with 5-aza-CdR or TSA might be a useful therapeutic strategy for EBV-induced human gastric cancer.

Apoptosis↗

PubMed2006

Globin genes transcriptional switching, chromatin structure and linked lessons to epigenetics in cancer: a comparative overview.

At the present time research situates differential regulation of gene expression in an increasingly complex scenario based on interplay between genetic and epigenetic information networks, which need to be highly coordinated. Here we describe in a comparative way relevant concepts and models derived from studies on the chicken alpha- and beta-globin group of genes. We discuss models for globin switching and mechanisms for coordinated transcriptional activation. A comparative overview of globin genes chromatin structure, based on their genomic domain organization and epigenetic components is presented. We argue that the results of those studies and their integrative interpretation may contribute to our understanding of epigenetic abnormalities, from beta-thalassemias to human cancer. Finally we discuss the interdependency of genetic-epigenetic components and the need of their mutual consideration in order to visualize the regulation of gene expression in a more natural context and consequently better understand cell differentiation, development and cancer.

Animals↗

PubMed2006

The PHD finger protein VRN5 functions in the epigenetic silencing of Arabidopsis FLC.

Vernalization, the acceleration of flowering by the prolonged cold of winter, ensures that plants flower in favorable spring conditions. During vernalization in Arabidopsis, cold temperatures repress FLOWERING LOCUS C (FLC) expression in a mechanism involving VERNALIZATION INSENSITIVE 3 (VIN3), and this repression is epigenetically maintained by a Polycomb-like chromatin regulation involving VERNALIZATION 2 (VRN2), a Su(z)12 homolog, VERNALIZATION 1 (VRN1), and LIKE-HETEROCHROMATIN PROTEIN 1. In order to further elaborate how cold repression triggers epigenetic silencing, we have targeted mutations that result in FLC misexpression both at the end of the prolonged cold and after subsequent development. This identified VERNALIZATION 5 (VRN5), a PHD finger protein and homolog of VIN3. Our results suggest that during the prolonged cold, VRN5 and VIN3 form a heterodimer necessary for establishing the vernalization-induced chromatin modifications, histone deacetylation, and H3 lysine 27 trimethylation required for the epigenetic silencing of FLC. Double mutant and FLC misexpression analyses reveal additional VRN5 functions, both FLC-dependent and -independent, and indicate a spatial complexity to FLC epigenetic silencing with VRN5 acting as a common component in multiple pathways.

Arabidopsis↗

PubMed2004

Granulocyte colony-stimulating factor generates epigenetic and genetic alterations in lymphocytes of normal volunteer donors of stem cells.

OBJECTIVE: Because the effect of granulocyte colony-stimulating factor (G-CSF), which is widely used for allogeneic stem cell transplantation, on DNA function and stability has not yet been unequivocally elucidated, the aim of this study was to determine whether G-CSF leads to epigenetic and/or genetic modifications. MATERIALS AND METHODS: Molecular cytogenetic techniques based on fluorescence in situ hybridization technology were used. RESULTS: Lymphocytes of G-CSF mobilized donors displayed epigenetic (altered replication timing of alleles) and genetic (aneuploidy) alterations similar to those observed in lymphocytes of cancer patients. Specifically, in the donors' lymphocytes, biallelically expressed genes (TP53 and AML1) and a repetitive noncoding DNA sequence associated with chromosome segregation (CEN17) showed loss of synchrony in allelic replication timing (allele-specific replication). Each displayed a highly asynchronous pattern of allelic replication similar to that characterizing monoallelic expressed genes. This non-locus-specific epigenetic phenomenon, which also affects DNA sequences associated with chromosome segregation, was accompanied by aneuploidy. Although the loss of replication synchrony in the lymphocytes of G-CSF mobilized donors was a transient epigenetic modification, aneuploidy remained unchanged. The G-CSF effect also was observed after G-CSF administration in vitro. 5-Azacytidine, a DNA methylation blocking agent, inhibited G-CSF in vitro induction of allele-specific replication. CONCLUSION: G-CSF, probably via changes in DNA methylation capacity, leads to cancer-characteristic DNA modifications in lymphocytes of normal mobilized donors.

Adolescent↗

PubMed2005

Epigenetic inheritance in Arabidopsis: selective silence.

Eukaryotic organisms have the remarkable ability to inherit states of gene activity without altering the underlying DNA sequence. This epigenetic inheritance can persist over thousands of years, providing an alternative to genetic mutations as a substrate for natural selection. Epigenetic inheritance might be propagated by differences in DNA methylation, post-translational histone modifications, and deposition of histone variants. Mounting evidence also indicates that small interfering RNA (siRNA)-mediated mechanisms play central roles in setting up and maintaining states of gene activity. Much of the epigenetic machinery of many organisms, including Arabidopsis, appears to be directed at silencing viruses and transposable elements, with epigenetic regulation of endogenous genes being mostly derived from such processes.

Arabidopsis↗

PubMed2005

Delving into the diversity of facultative heterochromatin: the epigenetics of the inactive X chromosome.

X chromosome inactivation represents one of the most dramatic examples of mono-allelic gene expression and long-term gene-silencing in mammals. The key regulatory molecule that triggers silencing is the Xist transcript, but little is known about its repressive action. Some progress has been made in deciphering the epigenetics of the inactive state that it triggers, however. During pre-implantation development, the inactive state is relatively labile. Later on, in the soma, the inactive state is highly stable and clonally heritable. This is ensured by the panoply of epigenetic modifications that characterize the inactive X and, presumably, is also a result of its spatio-temporal segregation. The inactive X chromosome has been associated with an increasing number of histone modifications, and several recent studies have implicated Polycomb group proteins in laying down some of these marks. Thanks to genetic and biochemical approaches to analyse these proteins, the epigenetic tapestry of the inactive X is just beginning to be unravelled. Lineage-specific differences provide a glimpse into the developmental complexity of the epigenetic marks that ensure the inactive state.

Animals↗

PubMed2006

[Epigenetics of the sperm cell].

In addition to genetic information, the spermatozoon carries another type of information, named epigenetic, which is not associated with variations of the DNA sequence. In somatic cells, it is now generally admitted that epigenetic information is not only regulated by DNA methylation but also involves modifications of the genome structure, or epigenome. During male germ cell maturation, the epigenome is globally re-organized, since most histones, which are associated to DNA in somatic cells, are removed and replaced by sperm specific nuclear proteins, the protamines, responsible for the tight compaction of the sperm DNA. However, a small proportion of histones, and probably other proteins, are retained within the sperm nucleus, and the structure of the sperm genome is actually heterogeneous. This heterogeneity of the sperm epigenome could support an epigenetic information, transmitted to the embryo, which could be crucial for its development. Although it is nowadays possible to appreciate the global structure of the sperm genome, the precise constitution of the sperm epigenome remains unknown. In particular, very recent data suggest that specific regions of the genome could be associated with particular proteins and define specific structures. This structural partitioning of the sperm genome could convey important epigenetic information, crucial for the embryo development.

DNA↗

PubMed2006

Pattern of expression of genes linked to epigenetic silencing in human breast cancer.

Epigenetic mechanisms such as DNA methylation are now recognized to play an important role in neoplasia. The aim of this study is to relate the pattern of expression of multiple cancer genes known to undergo epigenetic inactivation by promoter hypermethylation in breast cancer with histologic and outcome data. We used immunohistochemistry to study expression of the tumor suppressor gene p16, estrogen receptor (ER) alpha, ERbeta, progesterone receptor (PR), and the DNA repair gene MGMT (O6 -methylguanine-DNA methyltransferase) in a panel of 200 breast cancers. Methylation-specific polymerase chain reaction was used to confirm MGMT promoter methylation. Loss of expression of MGMT, ERalpha, ERbeta, PR, and p16 was observed in 19%, 24%, 13%, 40%, and 50% of cases, respectively. A significant correlation was seen between grade III tumor and loss of expression of ERalpha, ERbeta, PR (all P < .0001), and MGMT (P = .04), whereas loss of expression of p16 was associated with grades I and II tumors (P < .001). Cases that expressed 3 or less of the 5 proteins studied had significantly reduced survival (P = .0016). Methylation-specific polymerase chain reaction in a subset of 20 cancers showed DNA methylation associated with the loss of MGMT expression (P < .001). In conclusion, there is silencing of several key genes in breast cancer affecting molecular pathways involved in cell immortalization, DNA repair, and hormonal regulation, and this correlates significantly with risk of cancer-specific death. This expression profile could be linked to epigenetic events, and if so, these pathways have potential as targets for therapeutic strategies based on reversal of epigenetic silencing.

Adenocarcinoma↗

PubMed2005

The epigenetics of oral cancer.

Whilst genetic alterations in oral cancer have long been documented, the appreciation of epigenetic changes is more recent. Epigenetic changes alter expression of tumour suppressor genes without changes in DNA sequence. Epigenetic mechanisms such as DNA methylation, histone methylation and deacetylation have been shown to silence key genes involved in cell proliferation, differentiation and genome integrity, and clearly have a central role in oral cancer. The pattern of hypermethylation in any individual tumour can now be accurately determined, which may find application in molecular staging. In addition, current trials are evaluating the safety and efficacy of agents affecting epigenetic changes in cancer patients which hold some therapeutic promise.

Acetylation↗

PubMed2006

NORE1B, a candidate tumor suppressor, is epigenetically silenced in human hepatocellular carcinoma.

BACKGROUND/AIMS: In human hepatocellular carcinoma (HCC) the ras-proto-oncogene is rarely mutated. We therefore studied the possible inactivation of the putative tumor-suppressors and ras-associating proteins, NORE1A, NORE1B, and RASSF1A in HCCs by mutation or epigenetic gene silencing through promoter-CpG hypermethylation. METHODS: SSCP-analyses, sequencing, and methylation-specific PCR were performed in 28 fibrotic/cirrhotic livers and 40 HCCs. RESULTS: The sequence of NORE1A/B exhibited no deviations and that of the RASSF1A gene a non-silent polymorphism ( approximately 10% of cases) and a missense mutation (one HCC). Both alterations may affect the growth-inhibiting capability of RASSF1A. Epigenetic inactivation of NORE1B was found in 62% of the HCCs and in hepatocarcinoma-cell lines due to considerable promoter-methylation of the gene. Methylation was detected also for RASSF1A in HCCs and hepatocarcinoma cell-lines. As a result, 97% of the HCCs revealed epigenetic silencing of NORE1B, RASSF1A, or both. In contrast every third fibrotic/cirrhotic liver only exhibited silencing of one or both genes. CONCLUSIONS: The candidate tumor suppressor genes NORE1B and RASSF1A are epigenetically down-regulated alone in at least 62%, or in combination in 97% of the HCCs studied. This indicates a frequent and critical event in hepatocarcinogenesis, which may allow HCCs to subverse growth-control in the presence of an unaltered Ras.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Roles for nutrients in epigenetic events.

The field of epigenetics is the study of modifications of DNA and DNA-binding proteins that alter the structure of chromatin without altering the nucleotide sequence of DNA; some of these modifications may be associated with heritable changes in gene function. Nutrients play essential roles in the following epigenetic events. First, folate participates in the generation of S-adenosylmethionine, which acts as a methyl donor in the methylation of cytosines in DNA; methylation of cytosines is associated with gene silencing. Second, covalent attachment of biotin to histones (DNA-binding proteins) plays a role in gene silencing and in the cellular response to DNA damage. Third, tryptophan and niacin are converted to nicotinamide adenine dinucleotide, which is a substrate for poly(ADP-ribosylation) of histones and other DNA-binding proteins; poly(ADP-ribosylation) of these proteins participates in DNA repair and apoptosis. Here we present a novel procedure to map nutrient-dependent epigenetic marks in the entire genomes of any given species: the combined use of chromatin immunoprecipitation assays and DNA microarrays. This procedure is also an excellent tool to map the enzymes that mediate modifications of DNA and DNA-binding proteins in chromatin. Given the tremendous opportunities offered by the combined use of chromatin immunoprecipitation assays and DNA microarrays, the nutrition community can expect seeing a surge of information related to roles for nutrients in epigenetic events.

Base Sequence↗

PubMedDate not supplied

The application of epigenetic modifiers on the treatment of prostate and bladder cancer.

Prostate cancer and transitional cell carcinoma (TCC) of bladder are the 2 most common malignancies in the male adult urogenital system. Epigenetic gene silencing, particularly tumor suppressor genes, has become a new area of cancer research. Agents such as deoxyribonucleic acid methyltransferase inhibitors or histone deacetylase inhibitors are epigenetic modifiers that can restore gene expression and alter the malignant phenotype of cancer. They provide a new therapeutic avenue for prostate cancer and TCC. It is also likely that combination regimens using epigenetic modifiers with other classes of agents may have higher therapeutic efficacy for prostate cancer and TCC, especially metastatic and/or refractory cases. We review current knowledge of epigenetic event in prostate cancer and TCC, and discuss the possible clinical implications for these 2 diseases.

Carcinoma, Transitional Cell↗

PubMed2006

Epigenetic regulation of maspin expression in human ovarian carcinoma cells.

OBJECTIVE: Maspin expression is often deregulated in human cancer cells compared to their normal cells due to loss of epigenetic control. In contrast to normal human ovarian surface epithelial (HOSE) cells, ovarian carcinoma cells display a gain of maspin mRNA expression. The objective of this study was to determine whether gain of maspin expression in ovarian cancer is governed by epigenetic mechanisms. METHODS: We examined the cytosine methylation and chromatin accessibility status of the maspin promoter in normal HOSE cells and ovarian carcinoma cells with real-time RT-PCR, sodium bisulfite genomic sequencing, and chromatin accessibility assays. 5-Aza-2'-deoxycytidine (5-aza-dC) was used to induce demethylation of the maspin promoter. Ad p53 was used to induce transient overexpression of wild-type p53. RESULTS: Normal HOSE cells were maspin-negative in association with methylation of the maspin promoter. In the maspin-positive ovarian cancer cell lines, the maspin promoter was unmethylated. Increased maspin expression in ovarian carcinoma cells was accompanied by a more accessible chromatin structure in the maspin promoter. In the maspin-negative ovarian cancer cell line A222, maspin could be induced following 5-aza-dC treatment or by forced overexpression of p53. CONCLUSIONS: These results suggest that changes in cytosine methylation and chromatin accessibility play an important role in maspin expression in human ovarian carcinoma. Deregulation of maspin expression in ovarian cancer is due to loss of epigenetic control as has been shown in other cancers. This observation provides further evidence of the strict epigenetic control of the maspin gene.

Chromatin↗

PubMed2001

Biallelic inactivation of retinoic acid receptor beta2 gene by epigenetic change in breast cancer.

A growing body of evidence supports the hypotheses that retinoic acid receptor beta2 (RAR beta2) is a tumor suppressor gene. Although the loss of RAR beta2 expression has been reported in many malignant tumors, including breast cancer, the molecular mechanism is still poorly understood. We hypothesized that loss of RAR beta2 activity could result from multiple factors, including epigenetic modification and loss of heterozygosity (LOH). Using methylation-specific polymerase chain reaction and LOH analysis, we found that biallelic inactivation via epigenetic changes of both maternal and paternal alleles, or epigenetic modification of one allele combined with genetic loss of the remaining allele, could completely suppress RAR beta2 expression in breast cancer. Thus, it is possible that substantial numbers of human cancers arise through suppressor gene silencing via epigenetic mechanisms that inactivate both alleles. Because of this, chromatin-remodeling drugs may provide a novel strategy for cancer prevention and treatment.

Alleles↗