Cancer DNA Methylation: Molecular Mechanisms and Clinical Implications

McCabe, Michael T.; Brandes, Johann C.; Vertino, Paula M.

doi:10.1158/1078-0432.ccr-08-2784

Cited by 235 publications

(204 citation statements)

References 132 publications

(151 reference statements)

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“…Malignant cancer cells have been shown to exhibit major disruptions in their DNA methylation profiles, and these changes have also been shown to include aberrant hypermethylation or hypomethylation of gene CpG islands. 28 Here we employed an epigenetic strategy and compared the A253, SGT and HSG cell lines. The A253 and SGT cell lines were originally derived from a human submandibular gland tumor 21 , and salivary gland adenocarcinoma tissue, 29 and have been used to study secretory mechanisms such as chloride transport 30 and intracellular signal transduction pathways.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic modulation of the muscarinic type 3 receptor in salivary epithelial cells

Shin

Jin

Hwang

et al. 2015

Laboratory Investigation

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Muscarinic receptors, particularly the type 3 subtype (M3R), have an important role in exocrine secretion. M3R normally function in HSG cells originated from human submandibular gland ducts, but not in A253 and SGT cells, derived from human submandibular carcinoma and salivary gland adenocarcinoma. However, the underlying mechanism of this suppression has remained elusive. In this study, we examined whether M3R function is suppressed by epigenetic modulation of the receptor. To this end, we investigated the mRNA transcript and protein levels of the M3R using reverse transcriptase-PCR, western blot, and confocal microscopy analyses. Global DNA methylation assays, methylation-specific PCR, and bisulfite sequencing were also performed to understand the epigenetic status of the M3R CpG island. We found that A253 cells expressed all subtypes of muscarinic receptors, except M3R, on the mRNA level. However, treatment of cells with 5-aza-2 0 -deoxycytidine (5-Aza-CdR), a DNA-demethylating agent, increased the expression levels of both M3R mRNA transcript and protein in proportion to the incubation period. 5-Aza-CdR completely restored the carbacholinduced calcium response, which was not observed in untreated A253 cells. In untreated A253 cells, all CG pairs from the 1st to 14th were methylated and 5-Aza-CdR treatment demethylated one of the methylated CG pairs. We also examined the methylation pattern of M3R CpG island in human cancer tissue. Interestingly, the result was very similar to those of A253 cells. All CG pairs in M3R CpG island were also methylated. Another salivary gland tumor cell line, SGT, also showed the similar methylation pattern, heavy methylation in M3R CpG island. It is concluded that CpG island in M3R is hypermethylated in cancer cell lines and human cancer. Our results further suggest that 5-Aza-CdR could potentially be used to restore the function of M3R, suppressed in some cancer cell types. Epigenetic regulation by CpG methylation has an important role in tumorigenesis, and is also crucial to mounting a successful response to cancer therapy. CpG islands in DNA are methylated de novo in a tissue-specific manner, and the patterns of methylation are fixed in subsequent cell divisions by methyltransferase activity. 1 Recent studies have indicated that hypermethylation of CpG islands within the promoter and 5 0 regions of genes is an important epigenetic mechanism for suppressing gene expression. 2-4 DNA hypermethylation may directly affect the basal transcriptional machinery by altering the secondary structure of DNA and inducing chromosome remodeling through methyl group-binding proteins and histone deacetylase, thereby leading to transcriptional repression. 5 5-Aza-2 0 -deoxycytidine (5-Aza-CdR, decitabine) is a prodrug that has been shown to be phosphorylated, and thus activated, by deoxytidine kinase. 5-Aza-CdR is a nucleotide analog that is incorporated into DNA, where it irreversibly inactivates DNA methyltransferase (DNMT); 5-Aza-CdR is also an S-phase-specific agent. 6 The cytosine DNMT gen...

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Section: Discussionmentioning

confidence: 99%

Epigenetic modulation of the muscarinic type 3 receptor in salivary epithelial cells

Shin

Jin

Hwang

et al. 2015

Laboratory Investigation

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“…The methylated DNA can recruit the methyl-CpG-binding domain proteins Kaiso, MeCP2, and members of the MBD family (Fig. 2C), which recognize 5-methylcytosines in CpG islands and participate in chromatin silencing (McCabe et al, 2009).…”

Section: Dna Methylationmentioning

confidence: 99%

Epigenetic Mechanisms in Inflammation

2010

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Epigenetic modifications occur in response to environmental changes and play a fundamental role in gene expression following environmental stimuli. Major epigenetic events include methylation and acetylation of histones and regulatory factors, DNA methylation, and small non-coding RNAs. Diet, pollution, infections, and other environmental factors have profound effects on epigenetic modifications and trigger susceptibility to diseases. Despite a growing body of literature addressing the role of the environment on gene expression, very little is known about the epigenetic pathways involved in the modulation of inflammatory and anti-inflammatory genes. This review summarizes the current knowledge about epigenetic control mechanisms during the inflammatory response.

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“…For example, hypomethylation of intergenic regions can occur, leading to activation of transposable elements and increased genomic instability. Likewise, hypermethylation of the promoters of many tumor suppressor genes, such as retinoblastoma gene 1, E-cadherin, and RASSF1A often lead to loss of tumor suppressorfunction in certain cancer cells and tumors (12). Because DNMT1 and DNMT3B are overexpressed and amplified in numerous cancers, there has been considerable interest in the development of selective inhibitors.…”

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confidence: 99%

Identification of DNMT1 Selective Antagonists Using a Novel Scintillation Proximity Assay

Kilgore

Melito

et al. 2013

Journal of Biological Chemistry

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Background: DNA methylation contributes to the heritable regulation of gene expression. Results: Chemical inhibitors of DNA methyltransferase (DNMT) enzymes were identified. Conclusion: Several inhibitors nonspecifically inhibited multiple methyltransferases through generation of H 2 O 2 , but one compound showed selective inhibition of DNMT1 independent of the production of H 2 O 2 . Significance: Selective DNMT1 inhibitors will allow for more precise elucidation of the role of this enzyme in gene regulation.

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Cancer DNA Methylation: Molecular Mechanisms and Clinical Implications

Cited by 235 publications

References 132 publications

Epigenetic modulation of the muscarinic type 3 receptor in salivary epithelial cells

Epigenetic modulation of the muscarinic type 3 receptor in salivary epithelial cells

Epigenetic Mechanisms in Inflammation

Identification of DNMT1 Selective Antagonists Using a Novel Scintillation Proximity Assay

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