Investigating the Epigenetic Effects of a Prototype Smoke-Derived Carcinogen in Human Cells

Tommasi, Stefania; Kim, Sang-in; Zhong, Xueyan; Wu, Xiwei; Pfeifer, Gerd P.; Besaratinia, Ahmad

doi:10.1371/journal.pone.0010594

Cited by 17 publications

(22 citation statements)

References 49 publications

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“…In a study comparing peripheral blood DNA methylation profiles of smokers and nonsmokers, only one differentially methylated locus was found (Breitling et al 2011). An in vitro study of human lung cells chronically exposed to a tobacco carcinogen also showed little to no effect on DNA methylation profiles in treated vs. untreated cells (Tommasi et al 2010). In our genome-scale supervised approach, we noted only six sig- Cold Spring Harbor Laboratory Press on May 11, 2018 -Published by genome.cshlp.org Downloaded from nificantly differentially methylated genes between smokers and never-smokers, and of these only LGALS4 showed a corresponding down-regulation in gene expression in current smoker tumors.…”

Section: Discussionmentioning

confidence: 99%

Genome-scale analysis of DNA methylation in lung adenocarcinoma and integration with mRNA expression

Selamat¹,

Chung²,

Girard³

et al. 2012

Genome Res.

448

400

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Lung cancer is the leading cause of cancer death worldwide, and adenocarcinoma is its most common histological subtype. Clinical and molecular evidence indicates that lung adenocarcinoma is a heterogeneous disease, which has important implications for treatment. Here we performed genome-scale DNA methylation profiling using the Illumina Infinium HumanMethylation27 platform on 59 matched lung adenocarcinoma/non-tumor lung pairs, with genome-scale verification on an independent set of tissues. We identified 766 genes showing altered DNA methylation between tumors and non-tumor lung. By integrating DNA methylation and mRNA expression data, we identified 164 hypermethylated genes showing concurrent down-regulation, and 57 hypomethylated genes showing increased expression. Integrated pathways analysis indicates that these genes are involved in cell differentiation, epithelial to mesenchymal transition, RAS and WNT signaling pathways, and cell cycle regulation, among others. Comparison of DNA methylation profiles between lung adenocarcinomas of current and never-smokers showed modest differences, identifying only LGALS4 as significantly hypermethylated and down-regulated in smokers.LGALS4, encoding a galactoside-binding protein involved in cell-cell and cell-matrix interactions, was recently shown to be a tumor suppressor in colorectal cancer. Unsupervised analysis of the DNA methylation data identified two tumor subgroups, one of which showed increased DNA methylation and was significantly associated with KRAS mutation and to a lesser extent, with smoking. Our analysis lays the groundwork for further molecular studies of lung adenocarcinoma by identifying novel epigenetically deregulated genes potentially involved in lung adenocarcinoma development/progression, and by describing an epigenetic subgroup of lung adenocarcinoma associated with characteristic molecular alterations.

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Section: Discussionmentioning

confidence: 99%

Genome-scale analysis of DNA methylation in lung adenocarcinoma and integration with mRNA expression

Selamat¹,

Chung²,

Girard³

et al. 2012

Genome Res.

448

400

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“…We used the m ethylated CpG (mCG) i sland r ecovery a ssay (MIRA) in combination with microarray analysis (25,26) to globally profile DNA methylation in primary, senescent and immortalized MEFs. As a pull-down assay for enrichment of mCG islands, the MIRA is based on the ability of the methyl-CpG binding 2b (MBD2b) protein to bind methylated-CpG dinucleotides, while this reaction is enhanced in the presence of MBD3L1 protein (27).…”

Section: Methodsmentioning

confidence: 99%

“…As a pull-down assay for enrichment of mCG islands, the MIRA is based on the ability of the methyl-CpG binding 2b (MBD2b) protein to bind methylated-CpG dinucleotides, while this reaction is enhanced in the presence of MBD3L1 protein (27). The MIRA-enriched- and input (non-enriched) DNA fractions were amplified by polymerase chain reaction (PCR), and subsequently labeled and hybridized to the Roche NimbleGen mouse methylation microarrays (Roche NimbleGen Inc., Indianapolis, IN) to interrogate the entire CpG-island battery of the mouse genome (see Supplementary Data) (25,26). The accession number for DNA methylation microarray data is GSE39034.…”

Section: Methodsmentioning

confidence: 99%

Mammalian cells acquire epigenetic hallmarks of human cancer during immortalization

Tommasi

Zheng

Weninger

et al. 2012

Nucleic Acids Research

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Progression to malignancy requires that cells overcome senescence and switch to an immortal phenotype. Thus, exploring the genetic and epigenetic changes that occur during senescence/immortalization may help elucidate crucial events that lead to cell transformation. In the present study, we have globally profiled DNA methylation in relation to gene expression in primary, senescent and immortalized mouse embryonic fibroblasts. Using a high-resolution genome-wide mapping technique, followed by extensive locus-specific validation assays, we have identified 24 CpG islands that display significantly higher levels of CpG methylation in immortalized cell lines as compared to primary murine fibroblasts. Several of these hypermethylated CpG islands are associated with genes involved in the MEK–ERK pathway, one of the most frequently disrupted pathways in cancer. Approximately half of the hypermethylated targets are developmental regulators, and bind to the repressive Polycomb group (PcG) proteins, often in the context of bivalent chromatin in mouse embryonic stem cells. Because PcG-associated aberrant DNA methylation is a hallmark of several human malignancies, our methylation data suggest that epigenetic reprogramming of pluripotency genes may initiate cell immortalization. Consistent with methylome alterations, global gene expression analysis reveals that the vast majority of genes dysregulated during cell immortalization belongs to gene families that converge into the MEK–ERK pathway. Additionally, several dysregulated members of the MAP kinase network show concomitant hypermethylation of CpG islands. Unlocking alternative epigenetic routes for cell immortalization will be paramount for understanding crucial events leading to cell transformation. Unlike genetic alterations, epigenetic changes are reversible events, and as such, can be amenable to pharmacological interventions, which makes them appealing targets for cancer therapy when genetic approaches prove inadequate.

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“…This may be explained by the inhibition of enzyme-catalyzed transfer of methyl groups from S -adenosyl-L-methionine to cytosines, which is potentially caused by B a P-DNA adducts [44]. In contrast, a lack of change in global DNA methylation has also been reported in a number of in vitro experiments as well [43, 45–48]. However, sequence-specific hypo- and hyper-methylation was observed in p53-positive and p53-negative human breast cancer cell lines, primarily hypomethylation at DNA repetitive elements, in the absence of global DNA methylation changes [47].…”

Section: Epigenetic Effects Associated With Carcinogenic Chemicalsmentioning

confidence: 99%

Epigenetic alterations induced by genotoxic occupational and environmental human chemical carcinogens: A systematic literature review

Chappell

Pogribny

Guyton

et al. 2016

Mutation Research/Reviews in Mutation Research

142

105

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Accumulating evidence suggests that epigenetic alterations play an important role in chemically-induced carcinogenesis. Although the epigenome and genome may be equally important in carcinogenicity, the genotoxicity of chemical agents and exposure-related transcriptomic responses have been more thoroughly studied and characterized. To better understand the evidence for epigenetic alterations of human carcinogens, and the potential association with genotoxic endpoints, we conducted a systematic review of published studies of genotoxic carcinogens that reported epigenetic endpoints. Specifically, we searched for publications reporting epigenetic effects for the 28 agents and occupations included in Monograph Volume 100F of the International Agency for the Research on Cancer (IARC) that were classified as “carcinogenic to humans” (Group 1) with strong evidence of genotoxic mechanisms of carcinogenesis. We identified a total of 158 studies that evaluated epigenetic alterations for 12 of these 28 carcinogenic agents and occupations (1,3-butadiene, 4-aminobiphenyl, aflatoxins, benzene, benzidine, benzo[a]pyrene, coke production, formaldehyde, occupational exposure as a painter, sulfur mustard, and vinyl chloride). Aberrant DNA methylation was most commonly studied, followed by altered expression of non-coding RNAs and histone changes (totaling 85, 59 and 25 studies, respectively). For 3 carcinogens (aflatoxins, benzene and benzo[a]pyrene), 10 or more studies reported epigenetic effects. However, epigenetic studies were sparse for the remaining 9 carcinogens; for 4 agents, only 1 or 2 published reports were identified. While further research is needed to better identify carcinogenesis-associated epigenetic perturbations for many potential carcinogens, published reports on specific epigenetic endpoints can be systematically identified and increasingly incorporated in cancer hazard assessments.

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Investigating the Epigenetic Effects of a Prototype Smoke-Derived Carcinogen in Human Cells

Cited by 17 publications

References 49 publications

Genome-scale analysis of DNA methylation in lung adenocarcinoma and integration with mRNA expression

Genome-scale analysis of DNA methylation in lung adenocarcinoma and integration with mRNA expression

Mammalian cells acquire epigenetic hallmarks of human cancer during immortalization

Epigenetic alterations induced by genotoxic occupational and environmental human chemical carcinogens: A systematic literature review

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