Epigenetic control of programmed cell death: inhibition by 5-azacytidine of 1,25-dihydroxyvitamin D3-induced programmed cell death in C6.9 glioma cells (original) (raw)
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Cancers, 2011
Epigenetic mechanisms assist in maintaining gene expression patterns and cellular properties in developing and adult tissues. The molecular pathology of disease states frequently includes perturbation of DNA and histone methylation patterns, which can activate apoptotic pathways associated with maintenance of genome integrity. This perspective focuses on the pathways linking DNA methyltransferases and methyl-CpG binding proteins to apoptosis, and includes new bioinformatic analyses to characterize the evolutionary origin of two G/T mismatch-specific thymine DNA glycosylases, MBD4 and TDG.
DNA methylation and epigenetic inheritance
Methods, 2002
Mammalian cell lines silence genes at low frequency by the methylation of promoter sequences. These silent genes can be reactivated at high frequency by the demethylating agent 5-azacytidine (5-aza-CR). The inactive and active epigenetic states of such genes are stably inherited. A method for silencing genes is now available. It involves treatment of permeabilized cells with 5-methyl deoxycytidine triphosphate (5-methyl dCTP) which is incorporated into DNA. The methylation of promoter sequences has been confirmed using the bisulfite genomic sequencing procedure. Methylated oligonucleotides homologous to promoter sequences might be used to specifically target and silence given genes, but results so far have not been conclusive. Treatments that silence or reactivate genes by changing DNA methylation can be referred to as epimutagens, as distinct from mutagens that act by changing DNA sequences. The epimutagen 5-aza-CR reactivates genes but has little mutagenic activity, whereas standard mutagens (such as ethyl methane sulfonate and ultraviolet light) have little reactivation activity. Nevertheless, much more information is required about the effects of DNA-damaging agents in changing DNA methylation and gene activity and also about the role of epimutations in tumor progression.
Oncogene, 2007
The epigenetic silencing of tumor suppressor genes is a common event during carcinogenesis, and often involves aberrant DNA methylation and histone modification of gene regulatory regions, resulting in the formation of a transcriptionally repressive chromatin state. Two examples include the antimetastatic, tumor suppressor genes, desmocollin 3 (DSC3) and MASPIN, which are frequently silenced in this manner in human breast cancer. Treatment of the breast tumor cell lines MDA-MB-231 and UACC 1179 with 5-aza-2 0-deoxycytidine (5-aza-CdR) induced transcriptional reactivation of both genes in a dose-dependent manner. Importantly, DSC3 and MASPIN reactivation was closely and consistently linked with significant decreases in promoter H3 K9 di-methylation. Moreover, 5-aza-CdR treatment also resulted in global decreases in H3 K9 di-methylation, an effect that was linked to its ability to mediate dose-dependent, posttranscriptional decreases in the key enzyme responsible for this epigenetic modification, G9A. Finally, small interfering RNA (siRNA)-mediated knockdown of G9A and DNMT1 led to increased MASPIN expression in MDA-MB-231 cells, to levels that were supra-additive, verifying the importance of these enzymes in maintaining multiple layers of epigenetic repression in breast tumor cells. These results highlight an additional, complimentary mechanism of action for 5-aza-CdR in the reactivation of epigenetically silenced genes, in a manner that is independent of its effects on DNA methylation, further supporting an important role for H3 K9 methylation in the aberrant repression of tumor suppressor genes in human cancer.
Cancer and Metastasis Reviews, 2008
Cancer cells and tissues exhibit genome wide hypomethylation and regional hypermethylation. CpGmethylation of DNA (Me CpG-DNA) is defined as the formation of a CC covalent bond between the 5′-C of cytosine and the-CH 3 group of S-adenosylmethionine. Removal of the sole-CH 3 group from the methylated cytosine of DNA is one of the many ways of DNAdemethylation, which contributes to activation of transcription. The mechanism of demethylation, the candidate enzyme(s) exhibiting direct demethylase activity and associated cofactors are not firmly established. Genomewide hypomethylation can be obtained in several ways by inactivation of DNMT enzyme activity, including covalent trapping of DNMT by cytosine base analogues. Removal of methyl layer could also be occurred by excision of the 5-methyl cytosine base by DNA glycosylases. The importance of truly chemically defined direct demethylation of intact DNA in regulation of gene expression, development, cell differentiation and transformation are discussed in this contribution.
DNA methylation and cancer; A Review Article
Epigenetics is the study of the changes in gene expression that are heritable and do not involve a change in the DNA sequence. DNA methylation is one of the key epigenetic mechanisms that is clearly understood. DNA methylation is the process that add methyl group to the 5 th carbon atom of the cytosine base at CpG dinucleotides without changing the nucleotide sequence. Transcriptional silencing in X inactivation and genomic imprinting are two important epigenetic mechanisms where DNA methylation plays a major role. It is well known that DNA hypermethylation and hypomethylation are directly associated with tumor formation. Hypomethylation leads to the inappropriate and increased levels of gene expression in tumors. Trancriptional repression that is seen in cancers is also mostly due to hypermethylation. DNA methylation plays a major role in transcriptional silencing in X inactivation, genomic imprinting and tumor or cancer formation. Changes in the pattern of DNA methylation have been a consistent finding in cancer cells. DNA methylation plays an important role in the generation of mutations in human tumors. The high incidence of C-toT transitions found in the p53 tumor-suppressor gene. DNA methylation plays a crucial role in the regulation of gene expression and chromatin organization within normal eukaryotic cells. In cancer patterns of DNA methylation are altered with global hypomethylation and hypermethylation of a subset of CpG-dense gene-associated regions (CpG islands).
Leukemia Research, 1985
The effects of 5-AZA-2 '-deoxycytidine (5-AZA-CdR) on the induction of morphological and biochemical differentiation and inhibition of DNA methylation of human HE-60 myetiod leukemic cells were investigated. 5-AZA-CdR at concentrations of 0. I-1 I-tg ml -' for 48-h exposure produced significant morphological differentiation of HL-60 leukemic cells to a more mature phenotype, augmented the cell surface marker (OKMI) for mature granulocytes/ monocytes and also increased the superoxide anion production. Under these same conditions 5-AZA-CdR inhibited the synthesis of 5-methylcytosine in DNA suggesting that there is a correlation between the induction of differentiation and inhibition of DNA methylation. At concentrations of 5-AZA-CdR that inhibit DNA methylation there was a marked decrease in colonyformation suggesting that the antileukemic action of this analog is related to the methylation of DNA.
Increased expression of unmethylated CDKN2D by 5-aza-2′-deoxycytidine in human lung cancer cells
Oncogene, 2001
DNA hypermethylation of CpG islands in the promoter region of genes is associated with transcriptional silencing. Treatment with hypo-methylating agents can lead to expression of these silenced genes. However, whether inhibition of DNA methylation in¯uences the expression of unmethylated genes has not been extensively studied. We analysed the methylation status of CDKN2A and CDKN2D in human lung cancer cell lines and demonstrated that the CDKN2A CpG island is methylated, whereas CDKN2D is unmethylated. Treatment of cells with 5-aza-2'-deoxycytidine (5-Aza-CdR), an inhibitor of DNA methyltransferase 1, induced a dose and duration dependent increased expression of both p16 INK4a and p19 INK4d , the products of CDKN2A and CDKN2D, respectively. These data indicate that global DNA demethylation not only in¯uences the expression of methylated genes but also of unmethylated genes. Histone acetylation is linked to methylation induced transcriptional silencing. Depsipeptide, an inhibitor of histone deacetylase, acts synergistically with 5-Aza-CdR in inducing expression of p16 INK4a and p19 INK4d. However, when cells were treated with higher concentrations of 5-Aza-CdR and depsipeptide, p16 INK4a expression was decreased together with signi®cant suppression of cell growth. Interestingly, p19 INK4d expression was enhanced even more by the higher concentrations of 5-Aza-CdR and depsipeptide. Our data suggest that p19 INK4d plays a distinct role from other INK4 family members in response to the cytotoxicity induced by inhibition of DNA methylation and histone deacetylation. Oncogene (2001) 20, 7787 ± 7796.
DNA methylation: gene expression regulation
Folia Biologica et Oecologica, 2016
Epigenetic modifications are responsible for the modulation of gene expression without affecting the nucleotide sequence. The observed changes in transcriptional activity of genes in tumor tissue compared to normal tissue, are often the result of DNA methylation within the promoter sequences of these genes. This modification by attaching methyl groups to cytosines within CpG islands results in silencing of transcriptional activity of the gene, which in the case of tumor suppressor genes is manifested by abnormal cell cycle, proliferation and excessive destabilization of the repair processes. Further studies of epigenetic modifications will allow a better understanding of mechanisms of their action, including the interdependence between DNA methylation and activity of proteins crucial to the structure of chromatin and gene activity. Wider knowledge of epigenetic mechanisms involved in the process of malignant transformation and pharmacological regulation of the degree of DNA methylat...