DNA Methylation and Cancer

Kulis, Marta; Esteller, Manel

doi:10.1016/b978-0-12-380866-0.60002-2

Cited by 1,331 publications

(1,095 citation statements)

References 107 publications

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“…Folate deficiency and excess have been shown to affect DNA methylation in a gene, site, and cell-specific manner (Ly et al 2012). DNA methylation is an important epigenetic determinant in gene expression (an inverse relation except for few exceptions), in the maintenance of DNA integrity and stability, in chromatin modifications, and in the development of mutations (Kulis and Esteller 2010). DNA methylation of cytosine in the cytosine-guanine dinucleotide sequences (CpG) is a heritable, tissue-and species-specific, post-synthetic epigenetic modification of mammalian DNA (Kulis and Esteller 2010).…”

Section: Introductionmentioning

confidence: 99%

“…DNA methylation of cytosine in the cytosine-guanine dinucleotide sequences (CpG) is a heritable, tissue-and species-specific, post-synthetic epigenetic modification of mammalian DNA (Kulis and Esteller 2010). Seventy to 80 % of all CpG sites in human DNA are normally methylated (Kulis and Esteller 2010). However, this methylation occurs primarily in the bulk of the genome where CpG density is low, including exons, noncoding regions, and repeat DNA sites, and allows correct organization of chromatin in active and inactive states (Kulis and Esteller 2010).…”

Section: Introductionmentioning

confidence: 99%

“…However, this methylation occurs primarily in the bulk of the genome where CpG density is low, including exons, noncoding regions, and repeat DNA sites, and allows correct organization of chromatin in active and inactive states (Kulis and Esteller 2010). By contrast, most CpG-rich areas clustered in small stretches of DNA termed ''CpG islands'', which span the 5 0 end of approximately half of the human genes including the promoter, untranslated region, and exon 1, are unmethylated in normal cells, thereby allowing transcription (Herman and Baylin 2003;Kulis and Esteller 2010). When methylated, CpG islands can correlate with stable heritable transcriptional silencing (Herman and Baylin 2003;Kulis and Esteller 2010).…”

Section: Introductionmentioning

confidence: 99%

“…By contrast, most CpG-rich areas clustered in small stretches of DNA termed ''CpG islands'', which span the 5 0 end of approximately half of the human genes including the promoter, untranslated region, and exon 1, are unmethylated in normal cells, thereby allowing transcription (Herman and Baylin 2003;Kulis and Esteller 2010). When methylated, CpG islands can correlate with stable heritable transcriptional silencing (Herman and Baylin 2003;Kulis and Esteller 2010). DNA methylation is a dynamic process between active methylation, mediated by CpG DNA methyltransferases (DNMT) using SAM as the methyl donor, and removal of methyl groups from 5-methylcytosine residues by both passive and active mechanisms (Kulis and Esteller 2010;Li 2000).…”

Section: Introductionmentioning

confidence: 99%

“…DNA methylation is a dynamic process between active methylation, mediated by CpG DNA methyltransferases (DNMT) using SAM as the methyl donor, and removal of methyl groups from 5-methylcytosine residues by both passive and active mechanisms (Kulis and Esteller 2010;Li 2000). After transfer of the methyl group, SAM is converted to S-adenosylhomocysteine, a potent inhibitor of most SAM-dependent methyltransferases (Kulis and Esteller 2010;Li 2000).…”

Section: Introductionmentioning

confidence: 99%

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γ-Glutamyl hydrolase modulation significantly influences global and gene-specific DNA methylation and gene expression in human colon and breast cancer cells

et al. 2014

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c-Glutamyl hydrolase (GGH) plays an important role in folate homeostasis by catalyzing hydrolysis of polyglutamylated folate into monoglutamates. Polyglutamylated folates are better substrates for several enzymes involved in the generation of S-adenosylmethionine, the primary methyl group donor, and hence, GGH modulation may affect DNA methylation. DNA methylation is an important epigenetic determinant in gene expression, in the maintenance of DNA integrity and stability, and in chromatin modifications, and aberrant or dysregulation of DNA methylation has been mechanistically linked to the development of human diseases including cancer. Using a recently developed in vitro model of GGH modulation in HCT116 colon and MDA-MB-435 breast cancer cells, we investigated whether GGH modulation would affect global and gene-specific DNA methylation and whether these alterations were associated with significant gene expression changes. In both cell lines, GGH overexpression decreased global DNA methylation and DNA methyltransferase (DNMT) activity, while GGH inhibition increased global DNA methylation and DNMT activity. Epigenomic and gene expression analyses revealed that GGH modulation influenced CpG promoter DNA methylation and gene expression involved in important biological pathways including cell cycle, cellular development, and cellular growth and proliferation. Some of the observed altered gene expression appeared to be regulated by changes in CpG promoter DNA methylation. Our data suggest that the GGH modulation-induced changes in total intracellular folate concentrations and content of long-chain Electronic supplementary material The online version of this article

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

γ-Glutamyl hydrolase modulation significantly influences global and gene-specific DNA methylation and gene expression in human colon and breast cancer cells

et al. 2014

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TCF21 hypermethylation regulates renal tumor cell clonogenic proliferation and migration

et al. 2017

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We recently identified hypermethylation at the gene promoter of transcription factor 21 (TCF21) in clear cell sarcoma of the kidney (CCSK), a rare pediatric renal tumor. TCF21 is a transcription factor involved in tubular epithelial development of the kidney and is a candidate tumor suppressor. As there are no in vitro models of CCSK, we employed a well‐established clear cell renal cell carcinoma (ccRCC) cell line, 786‐O, which also manifests high methylation at the TCF21 promoter, with consequent low TCF21 expression. The tumor suppressor function of TCF21 has not been functionally addressed in ccRCC cells; we aimed to explore the functional potential of TCF21 expression in ccRCC cells in vitro. 786‐O clones stably transfected with either pBABE‐TCF21‐HA construct or pBABE vector alone were functionally analyzed. We found that ectopic expression of TCF21 in 786‐O cells results in a trend toward decreased cell proliferation (not significant) and significantly decreased migration compared with mock‐transfected 786‐O cells. Although the number of colonies established in colony formation assays was not different between 786‐O clones, colony size was significantly reduced in 786‐O cells expressing TCF21. To investigate whether the changes in migration were due to epithelial‐to‐mesenchymal transition changes, we interrogated the expression of selected epithelial and mesenchymal markers. Although we observed upregulation of mRNA and protein levels of epithelial marker E‐cadherin in clones overexpressing TCF21, this did not result in surface expression of E‐cadherin as measured by fluorescence‐activated cell sorting and immunofluorescence. Furthermore, mRNA expression of the mesenchymal markers vimentin (VIM) and SNAI1 was not significantly decreased in TCF21‐expressing 786‐O cells, while protein levels of VIM were markedly decreased. We conclude that re‐expression of TCF21 in renal cancer cells that have silenced their endogenous TCF21 locus through hypermethylation results in reduced clonogenic proliferation, reduced migration, and reduced mesenchymal‐like characteristics, suggesting a tumor suppressor function for transcription factor 21.

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Biomarker potential of ST6GALNAC3 and ZNF660 promoter hypermethylation in prostate cancer tissue and liquid biopsies

et al. 2018

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Current diagnostic and prognostic tools for prostate cancer (PC) are suboptimal, leading to overdiagnosis and overtreatment. Aberrant promoter hypermethylation of specific genes has been suggested as novel candidate biomarkers for PC that may improve diagnosis and prognosis. We here analyzed ST6GALNAC3 and ZNF660 promoter methylation in prostate tissues, and ST6GALNAC3,ZNF660,CCDC181, and HAPLN3 promoter methylation in liquid biopsies. First, using four independent patient sample sets, including a total of 110 nonmalignant (NM) and 705 PC tissue samples, analyzed by methylation‐specific qPCR or methylation array, we found that hypermethylation of ST6GALNAC3 and ZNF660 was highly cancer‐specific with areas under the curve (AUC) of receiver operating characteristic (ROC) curve analysis of 0.917–0.995 and 0.846–0.903, respectively. Furthermore, ZNF660 hypermethylation was significantly associated with biochemical recurrence in two radical prostatectomy (RP) cohorts of 158 and 392 patients and remained significant also in the subsets of patients with Gleason score ≤7 (univariate Cox regression and log‐rank tests, P < 0.05), suggesting that ZNF660 methylation analysis can potentially help to stratify low‐/intermediate‐grade PCs into indolent vs. more aggressive subtypes. Notably, ZNF660 hypermethylation was also significantly associated with poor overall and PC‐specific survival in the RP cohort (n = 158) with long clinical follow‐up available. Moreover, as proof of principle, we successfully detected highly PC‐specific hypermethylated circulating tumor DNA (ctDNA) for ST6GALNAC3,ZNF660,HAPLN3, and CCDC181 in liquid biopsies (serum) from 27 patients with PC vs. 10 patients with BPH, using droplet digital methylation‐specific PCR analysis. Finally, we generated a three‐gene (ST6GALNAC3/CCDC181/HAPLN3) ctDNA hypermethylation model, which detected PC with 100% specificity and 67% sensitivity. In conclusion, we here for the first time demonstrate diagnostic biomarker potential of ST6GALNAC3 and ZNF660 methylation, as well as prognostic biomarker potential of ZNF660. Furthermore, we show that hypermethylation of four genes can be detected in ctDNA in liquid biopsies (serum) from patients with PC.

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DNA Methylation and Cancer

Cited by 1,331 publications

References 107 publications

γ-Glutamyl hydrolase modulation significantly influences global and gene-specific DNA methylation and gene expression in human colon and breast cancer cells

γ-Glutamyl hydrolase modulation significantly influences global and gene-specific DNA methylation and gene expression in human colon and breast cancer cells

TCF21 hypermethylation regulates renal tumor cell clonogenic proliferation and migration

Biomarker potential of ST6GALNAC3 and ZNF660 promoter hypermethylation in prostate cancer tissue and liquid biopsies

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