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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Let me summarize by reviewing a model which is meant to raise as many questions as it answers (Fig. 2). What I have discussed today are data suggesting that during progression of solid tumors, like colon cancer, an increased cellular DNA methylating capacity characterizes the initial stages of multi-clonal hyperplasia. Despite this increase, the altered pattern of DNA methylation which subsequently emerges is largely manifest by a widespread hypomethylation of DNA. However, on a more regional basis, areas of hypermethylation appear which can affect strategic areas such as normally unmethylated CpG islands. These shifted DNA methylation patterns have the capacity to both follow, or cause, chromatin changes that can both directly silence genes critical for normal cell maturation--and/or participate in the structural chromosome changes which constitute genetic instability during tumor progression (Fig. 2). I suggest that one must view these changes as an interchangeable cycle of events during tumor progression. The chromatin changes and abnormal methylation patterns can drive one another with increasingly deleterious effects as the malignant phenotype emerges (reviewed in Baylin, 1991). What are the molecular events that would initiate the above dynamics? A working construct model is shown in Fig. 3. As discussed for the normal adult cell, there is a delicate balance between the strategic location of DNA MTase, regulation of this enzyme, and rate of DNA synthesis at replication forks (top panel, Fig. 3). In pre-neoplastic and cancer cells, perhaps failure of cells to exit the cell cycle and halt DNA replication, facilitates some sort of pressure to increase cellular DNA methyltransferase activity (bottom panel, Fig. 3). This increase may involve loss of feedback inhibition of the enzyme during the post DNA replication phase. There are also probable structural alterations in the nucleus which may alter the geographic relationship between the DNA replication fork and DNA MTase. In consequence, many DNA areas that should be getting methylated do not, and novel areas of methylation also arise. This cycle of events leads to the imbalance of DNA methylation that I have talked about. Future investigations of these possibilities, and of their specific consequences for alterations of gene expression and chromosome structure, may reveal a key molecular step underlying virtually all stages of tumor progression.
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PMID:Abnormal regional hypermethylation in cancer cells. 151 32

Epigenetic alterations in the genome of tumor cells have attracted considerable attention since the discovery of widespread alterations in DNA methylation of colorectal cancers over 10 years ago. However, the mechanism of these changes has remained obscure. el-Deiry and coworkers [el-Deiry, W. S., Nelkin, B. D., Celano, P., Yen, R. C., Falco, J. P., Hamilton, S. R. & Baylin, S. B. (1991) Proc. Natl. Acad. Sci. USA 88, 3470-3474], using a quantitative reverse transcription-PCR assay, reported 15-fold increased expression of DNA methyltransferase (MTase) in colon cancer, compared with matched normal colon mucosa, and a 200-fold increase in MTase mRNA levels compared with mucosa of unaffected patients. These authors suggested that increases in MTase mRNA levels play a direct pathogenetic role in colon carcinogenesis. To test this hypothesis, we developed a sensitive quantitative RNase protection assay of MTase, linear over three orders of magnitude. Using this assay on 12 colorectal carcinomas and matched normal mucosal specimens, we observed a 1.8- to 2.5-fold increase in MTase mRNA levels in colon carcinoma compared with levels in normal mucosa from the same patients. There was no significant difference between the normal mucosa of affected and unaffected patients. Furthermore, when the assay was normalized to histone H4 expression, a measure of S-phase-specific expression, the moderate increase in tumor MTase mRNA levels was no longer observed. These data are in contrast to the previously reported results, and they indicate that changes in MTase mRNA levels in colon cancer are nonspecific and compatible with other markers of cell proliferation.
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PMID:Limited up-regulation of DNA methyltransferase in human colon cancer reflecting increased cell proliferation. 881 6

CDX1 is a homeobox protein that inhibits proliferation of intestinal epithelial cells and regulates intestine-specific genes involved in differentiation. CDX1 expression is developmentally and spatially regulated, and its expression is aberrantly down-regulated in colorectal cancers and colon cancer-derived cell lines. However, very little is known about the molecular mechanism underlying the regulation of CDX1 gene expression. In this study, we characterized the CDX1 gene structure and identified that its gene promoter contained a typical CpG island with a CpG observed/expected ratio of 0.80, suggesting that the CDX1 gene is a target of aberrant methylation. Alterations of DNA methylation in the CDX1 gene promoter were investigated in a series of colorectal cancer cell lines. Combined Bisulfite Restriction Analysis (COBRA) and bisulfite sequencing analysis revealed that the CDX1 promoter is methylated in CDX1 non-expressing colorectal cancer cell lines but not in human normal colon tissue and T84 cells, which express CDX1. Treatment with 5'-aza-2'-deoxycytidine (5-azaC), a DNA methyltransferase inhibitor, induced CDX1 expression in the colorectal cancer cell lines. Furthermore, de novo methylation was determined by establishing stably transfected clones of the CDX1 promoter in SW480 cells and demethylation by 5-azaC-activated reporter gene expression. These results indicate that aberrant methylation of the CpG island in the CDX1 promoter is one of the mechanisms that mediate CDX1 down-regulation in colorectal cancer cell lines.
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PMID:DNA methylation down-regulates CDX1 gene expression in colorectal cancer cell lines. 1212 93

Transcriptional silencing by CpG island methylation is a prevalent mechanism of tumor-suppressor gene suppression in cancers. Genetic experiments have defined the importance of the DNA methyltransferase Dnmt1 for the maintenance of methylation in mouse cells and its role in neoplasia. In human bladder cancer cells, selective depletion of DNMT1 with antisense inhibitors has been shown to induce demethylation and reactivation of the silenced tumor-suppressor gene CDKN2A. In contrast, targeted disruption of DNMT1 alleles in HCT116 human colon cancer cells produced clones that retained CpG island methylation and associated tumor-suppressor gene silencing, whereas HCT116 clones with inactivation of both DNMT1 and DNMT3B showed much lower levels of DNA methylation, suggesting that the two enzymes are highly cooperative. We used a combination of genetic (antisense and siRNA) and pharmacologic (5-aza-2'-deoxycytidine) inhibitors of DNA methyl transferases to study the contribution of the DNMT isotypes to cancer-cell methylation. Selective depletion of DNMT1 using either antisense or siRNA resulted in lower cellular maintenance methyltransferase activity, global and gene-specific demethylation and re-expression of tumor-suppressor genes in human cancer cells. Specific depletion of DNMT1 but not DNMT3A or DNMT3B markedly potentiated the ability of 5-aza-2'-deoxycytidine to reactivate silenced tumor-suppressor genes, indicating that inhibition of DNMT1 function is the principal means by which 5-aza-2'-deoxycytidine reactivates genes. These results indicate that DNMT1 is necessary and sufficient to maintain global methylation and aberrant CpG island methylation in human cancer cells.
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PMID:DNMT1 is required to maintain CpG methylation and aberrant gene silencing in human cancer cells. 1249 60

The potential anticancer activities of histone deacetylase (HDAC) inhibitors and DNA methyltransferase (DNMT) inhibitors have been extensively studied in recent years. HDAC inhibitors suppress the activities of multiple HDACs, leading to an increase in histone acetylation. This histone acetylation induces an enhancement of the expression of specific genes that elicit extensive cellular morphologic and metabolic changes, such as growth arrest, differentiation and apoptosis. DNMT inhibitors, such as 5-aza-cytidine (5-aza-CR) and 5-aza-2'-deoxycytidine (5-aza-CdR) are also widely studied because DNA hypomethylation induces the re-activation of tumor suppressor genes that are silenced by methylation-mediated mechanisms. Recently, the combination of HDAC inhibitors or demethylating agents with other chemo-therapeutics has gained increasing interest as a possible molecularly targeted therapeutic strategy. In particular, the combination of HDAC inhibitors with demethylating agents has become attractive since histones are connected to DNA by both physical and functional interactions. To date, the accumulating evidence has confirmed the hypothesis that the combination of HDAC and DNMT inhibition is very effective (and synergistic) in inducing apoptosis, differentiation and/or cell growth arrest in human lung, breast, thoracic, leukemia and colon cancer cell lines. This review will discuss the in vitro effects of HDAC inhibitors, such as trichostatin A (TSA), sodium butyrate, depsipeptide (FR901228, FK228), valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA), and the demethylating agent, 5-aza-CdR used alone and in combination treatment of human cancer cells and the possible mechanisms involved.
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PMID:The interaction of histone deacetylase inhibitors and DNA methyltransferase inhibitors in the treatment of human cancer cells. 1276 77

In addition to its action as a topoisomerase II poison, mitoxantrone is activated by formaldehyde to bind DNA, forming DNA-adducts specifically at 5'CpG and CpA sequences, with an enhancement of adducts at methylated CpG sites. The butyric acid prodrug, AN-9 (pivaloyloxymethyl butyrate), releases formaldehyde upon cellular hydrolysis and our previous studies have shown that mitoxantrone acts synergistically with AN-9 in cytotoxicity assays. In this paper, we investigated the impact of methylation levels in the cell on mitoxantrone-induced cytotoxicity using the colon cancer cell line HCT116 and its derived DNA methyltransferase (DNMT) 1 and DNMT 3a knockout (DKO8) cell line. We found that decreased methylation levels in the DNMT-null cells led to at least a 2-fold reduction in mitoxantrone-induced cytotoxicity. Next, we studied the impact of mitox-antrone alone, and in combination with AN-9, on hypermethylated genes and their mRNA expression in breast cancer cells. Using methylation-specific PCR and RT-PCR, we found that mitoxantrone treatment of breast cancer cell lines resulted in demethylation of the 14.3.3s, Cyclin D2 and ERa genes, followed by re-expression of their mRNA. The effect of mitoxantrone on re-expression of key genes involved in cell cycle regulation, and ensuing death of the cells may be an additional, previously undiscovered mechanism of action of mitoxantrone.
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PMID:Mitoxantrone mediates demethylation and reexpression of cyclin d2, estrogen receptor and 14.3.3sigma in breast cancer cells. 1287 62

Hypermethylation of CpG islands in the promoter regions is an important mechanism to silence the expression of many important genes in cancer. The hypermethylation status is passed to the daughter cells through the methylation of the newly synthesized DNA strand by 5-cytosine DNA methyltransferase (DNMT). We report herein that (-)-epigallocatechin-3-gallate (EGCG), the major polyphenol from green tea, can inhibit DNMT activity and reactivate methylation-silenced genes in cancer cells. With nuclear extracts as the enzyme source and polydeoxyinosine-deoxycytosine as the substrate, EGCG dose-dependently inhibited DNMT activity, showing competitive inhibition with a K(i) of 6.89 microM. Studies with structural analogues of EGCG suggest the importance of D and B ring structures in the inhibitory activity. Molecular modeling studies also support this conclusion, and suggest that EGCG can form hydrogen bonds with Pro(1223), Glu(1265), Cys(1225), Ser(1229), and Arg(1309) in the catalytic pocket of DNMT. Treatment of human esophageal cancer KYSE 510 cells with 5-50 microM of EGCG for 12-144 h caused a concentration- and time-dependent reversal of hypermethylation of p16(INK4a), retinoic acid receptor beta (RARbeta), O(6)-methylguanine methyltransferase (MGMT), and human mutL homologue 1 (hMLH1) genes as determined by the appearance of the unmethylation-specific bands in PCR. This was accompanied by the expression of mRNA of these genes as determined by reverse transcription-PCR. The re-expression of RARbeta and hMLH1 proteins by EGCG was demonstrated by Western blot. Reactivation of some methylation-silenced genes by EGCG was also demonstrated in human colon cancer HT-29 cells, esophageal cancer KYSE 150 cells, and prostate cancer PC3 cells. The results demonstrate for the first time the inhibition of DNA methylation by a commonly consumed dietary constituent and suggest the potential use of EGCG for the prevention or reversal of related gene-silencing in the prevention of carcinogenesis.
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PMID:Tea polyphenol (-)-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. 1463 67

The role of the primary mammalian DNA methyltransferase, DNMT1, in maintaining CpG island methylation in human colon cancer cells has recently been questioned. This controversy has arisen from discrepancies between genetic knockout and RNA interference-mediated knockdown studies. Here, we re-examined the RNA interference-based approach and found that hypermethylation of single-copy genes is maintained in cells transiently and stably depleted of DNMT1.
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PMID:CpG island hypermethylation is maintained in human colorectal cancer cells after RNAi-mediated depletion of DNMT1. 1515 41

Folate is an essential co-factor in the remethylation of homocysteine to methionine, thereby ensuring the supply of S-adenosylmethionine, the methyl group donor for most biological methylations, including that of DNA. Aberrant patterns and dysregulation of DNA methylation are consistent events in carcinogenesis and hence, DNA methylation is considered to be mechanistically related to the development of cancer. Folate deficiency appears to increase the risk of several malignancies, and aberrant DNA methylation has been considered to be a leading mechanism by which folate deficiency enhances carcinogenesis. Although diets deficient in methyl group donors (choline, folate, methionine and vitamin B12) have been consistently observed to induce DNA hypomethylation, the effect of an isolated folate deficiency on DNA methylation remains highly controversial and unresolved. Whether or not isolated folate deficiency can modulate DNA methylation is an important issue because it would establish a mechanistic link between folate deficiency and cancer. We examined the effects of isolated folate deficiency on methionine cycle intermediates, genomic and site-specific DNA methylation and DNA methyltransferase in an in vitro model of folate deficiency, using untransformed NIH/3T3 and CHO-K1 cells, and human HCT116 and Caco-2 colon cancer cells. Our data demonstrate that the effect of folate deficiency on the methionine cycle pathway and DNA methylation in these cells is highly complex and appears to depend on the cell type and stage of transformation, and may be gene and site-specific. The direction of changes of methionine cycle intermediates in response to folate deficiency is not uniformly consistent with the known biochemical effect of folate on the methionine cycle pathway. Moreover, the effect of folate deficiency on DNA methylation appears to be mediated by both methionine cycle intermediate-dependent and independent pathways.
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PMID:Cell and stage of transformation-specific effects of folate deficiency on methionine cycle intermediates and DNA methylation in an in vitro model. 1569 36

GEM-231 is an 18-mer hybrid oligonucleotide under development by Hybridon for the potential treatment of cancer. This compound was initially developed for colon cancer [256660], and progressed to phase II trials in October 1998 [301009]. Hybridon initiated a phase I dose-escalation study enrolling up to 25 patients with refractory solid tumors, in January 1998 at the Lombardi Cancer Center, Georgetown University Medical Center [275860]. GEM-231 was well tolerated in multiple, escalating doses, and that high plasma levels could be safely achieved [301009]. In addition to antitumor effects, when used as a single agent in animal tumor models, GEM-231 has also demonstrated potentiation of the effects of certain conventional cytotoxic chemotherapy drugs [230699]. Hybridon is conducting studies of the DNA methyltransferase gene and has identified specific sequences on mRNA as targets for chemically-modified antisense oligonucleotides. Hybridon has synthesized compounds that alter methylation of cultured human cancer cells and inhibit their ability to grow in cell culture and inhibit tumor formation in mice [191303]. The work is being carried out in collaboration with McGill University in Montreal and as part of a joint venture called MethylGene, set up by Hybridon and private investors. GEM-231 and other oligonucleotides were claimed in WO- 09515378. Hybridon has been issued with two US patents, US- 05652355 and US-05562356, claiming chemically advanced, mixed-backbone oligonucleotides. The first claims mixed backbone 'hybrid' oligonucleotides, which are second generation chemistries, comprising an internal segment of modified DNA flanked by segments of modified RNA (2'-O-methyl substituted). The other claims mixed backbone 'inverted hybrid' oligonucleotides, which comprises an internal segment of naturally-linked, 2'-O-substituted RNA flanked by modified DNA segments [257135].
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PMID:GEM-231 (Hybridon). 1604 67


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