DNA Methylation in Cancer and Aging

Klutstein, Michael; Nejman, Deborah; Greenfield, Razi; Cedar, Howard

doi:10.1158/0008-5472.can-15-3278

Cited by 700 publications

(521 citation statements)

References 33 publications

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“…Intriguingly, the chromatin signature of DNA hypomethylation in cancer was substantially different, being primarily enriched in the posttranslational repressive histone modification H3K9me3, a relationship that has been investigated in colon and breast cancer (Berman et al., 2011; Hon et al., 2012). This observation might be conceptually relevant because DNA methylation has been proposed to be a molecular link between aging and cancer (Fraga, Agrelo & Esteller, 2007; Klutstein, Nejman, Greenfield & Cedar, 2016). However, our results suggest that the role of DNA methylation as a possible link between aging and cancer is more complex than previously proposed.…”

Section: Discussionmentioning

confidence: 98%

Distinct chromatin signatures of DNA hypomethylation in aging and cancer

et al. 2018

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SummaryCancer is an aging‐associated disease, but the underlying molecular links between these processes are still largely unknown. Gene promoters that become hypermethylated in aging and cancer share a common chromatin signature in ES cells. In addition, there is also global DNA hypomethylation in both processes. However, the similarity of the regions where this loss of DNA methylation occurs is currently not well characterized, and it is unknown if such regions also share a common chromatin signature in aging and cancer. To address this issue, we analyzed TCGA DNA methylation data from a total of 2,311 samples, including control and cancer cases from patients with breast, kidney, thyroid, skin, brain, and lung tumors and healthy blood, and integrated the results with histone, chromatin state, and transcription factor binding site data from the NIH Roadmap Epigenomics and ENCODE projects. We identified 98,857 CpG sites differentially methylated in aging and 286,746 in cancer. Hyper‐ and hypomethylated changes in both processes each had a similar genomic distribution across tissues and displayed tissue‐independent alterations. The identified hypermethylated regions in aging and cancer shared a similar bivalent chromatin signature. In contrast, hypomethylated DNA sequences occurred in very different chromatin contexts. DNA hypomethylated sequences were enriched at genomic regions marked with the activating histone posttranslational modification H3K4me1 in aging, while in cancer, loss of DNA methylation was primarily associated with the repressive H3K9me3 mark. Our results suggest that the role of DNA methylation as a molecular link between aging and cancer is more complex than previously thought.

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Section: Discussionmentioning

confidence: 98%

Distinct chromatin signatures of DNA hypomethylation in aging and cancer

et al. 2018

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“…It has been over 40 years since abnormal DNA methylation was first identified in tumor cells (31). Hypomethylation and gene-specific hypermethylation have since been observed in all detected tumor types (32). Currently, DNA demethylation drugs including decitabine and azacytidine are clinically used to treat myelodysplastic syndrome (33).…”

Section: Discussionmentioning

confidence: 99%

Casticin inhibits the activity of transcription factor Sp1 and the methylation of RECK in MGC803 gastric cancer cells

Yang

Huang

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. The present study investigated the effect of casticin on reversion-inducing-cysteine-rich protein with kazal motifs (RECK) gene expression and intracellular methylation levels in MGC803 gastric cancer cells. Cells were treated with 1, 10 and 30 µmol/l casticin. Western blotting and reverse transcription-quantitative polymerase chain reaction assays were performed to determine the protein expression and mRNA levels of RECK and DNA methyltransferase 1 (DNMT1), respectively. High-performance liquid chromatography coupled to electrospray ionization tandem mass spectrometry was used to detect RECK methylation. In addition, MGC803 cell proliferation was measured by an MTT assay and the DNA-binding activity of transcription factor Sp1 was determined using an enzyme-linked immunosorbent assay. The results demonstrated that treatment with 1, 10 and 30 µmol/l casticin significantly increased RECK protein expression and mRNA levels. In addition, casticin (30 µmol/l) decreased RECK promoter methylation levels by 31%, global DNA methylation levels by 39% and nuclear methylation activity by 71.6%. Furthermore, casticin downregulated the mRNA levels and protein expression of DNMT1. The MTT assay demonstrated that MGC803 cell proliferation was inhibited by casticin treatment and DNA binding assays indicated that casticin reduced the DNA-binding activity of Sp1. The present study therefore indicated that casticin inhibits the proliferation of gastric cancer MGC803 cells by upregulating RECK gene expression and reducing intracellular methylation levels.

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“…There is now considerable evidence demonstrating that abnormal methylation in normal tissues actually precedes the onset of tumors (11), and this early marker can be observed in individual crypts of the colon (28), in aging stem cells from the hematopoietic system (13) and in skin (29), raising the possibility that tumors themselves may evolve from normal cells that have already undergone excess de novo modification (30). In keeping with this idea, we have shown that tissue methylation is concentrated in a small number of individual CpG-island molecules, perhaps indicative of a fraction of cells that have undergone abnormal methylation (Table 1 and Fig.…”

Section: Significancementioning

confidence: 99%

Contribution of epigenetic mechanisms to variation in cancer risk among tissues

Klutstein

Moss

Kaplan

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Recently, it was suggested that tissue variation in cancer risk originates from differences in the number of stem-cell divisions underlying each tissue, leading to different mutation loads. We show that this variation is also correlated with the degree of aberrant CpG island DNA methylation in normal cells. Methylation accumulates during aging in a subset of molecules, suggesting that the epigenetic landscape within a founder-cell population may contribute to tumor formation.

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DNA Methylation in Cancer and Aging

Cited by 700 publications

References 33 publications

Distinct chromatin signatures of DNA hypomethylation in aging and cancer

Distinct chromatin signatures of DNA hypomethylation in aging and cancer

Casticin inhibits the activity of transcription factor Sp1 and the methylation of RECK in MGC803 gastric cancer cells

Contribution of epigenetic mechanisms to variation in cancer risk among tissues

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