Comparison of global DNA methylation profiles in replicative versus premature senescence

Zhang, Wenjuan; Ji, Weidong; Yang, Jianping; Liu, Yang; Chen, Wen; Zhuang, Zhixiong

doi:10.1016/j.lfs.2008.07.015

Cited by 58 publications

(42 citation statements)

References 17 publications

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“…Second, they could act as transcriptional repressors of CDKN1A gene, modulating p21 CIP1 transcription [54,55]. It is interesting to note that while the level of DNMTs increases in middle-aged human fibroblasts, it decreases in senescent fibroblasts [54,59]. This supports the role of DNMTs both in progressive telomere shortening in non-senescent cells and the subsequent activation of CD-KN1A transcription in senescent cells.…”

Section: Ink4amentioning

confidence: 67%

Senescence and p130/Rbl2: a new beginning to the end

et al. 2009

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Senescence is the process of cellular aging dependent on the normal physiological functions of non-immortalized cells. With increasing data being uncovered in this field, the complex molecular web regulating senescence is gradually being unraveled. Recent studies have suggested two main phases of senescence, the triggering of senescence and the maintenance of senescence. Each has been supported by data implying precise roles for DNA methyltransferases, reactive oxygen species and other factors. We will first summarize the data supporting these claims and then highlight the specific role that we hypothesize that p130/Rbl2 plays in the modulation of the senescence process.

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Section: Ink4amentioning

confidence: 67%

Senescence and p130/Rbl2: a new beginning to the end

et al. 2009

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“…In some tumor models, such as oral squamous-cell carcinoma or heptocellular carcinoma, 5-aza-dC induces cancer cell senescence (11,12). This has led to the hypothesis that either DNA hypomethylation or an alteration of the DNA structure might be involved in senescence induction (8,32). Therefore, it might be reasoned that compounds with DNMTi activity generally induce tumor cell senescence by DNA demethylation.…”

Section: Discussionmentioning

confidence: 99%

Differential Induction of Apoptosis and Senescence by the DNA Methyltransferase Inhibitors 5-Azacytidine and 5-Aza-2′-Deoxycytidine in Solid Tumor Cells

Venturelli

Berger

Weiland

et al. 2013

Molecular Cancer Therapeutics

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Epigenetic alterations are a hallmark of cancer that govern the silencing of genes. Up to now, 5-azacytidine (5-aza-CR, Vidaza) and 5-aza-2 0 -deoxycytidine (5-aza-dC, Dacogen) are the only clinically approved DNA methyltransferase inhibitors (DNMTi). Current effort tries to exploit DNMTi application beyond acute leukemia or myelodysplastic syndrome, especially to solid tumors. Although both drugs only differ by a minimal structural difference, they trigger distinct molecular mechanisms that are highly relevant for a rational choice of new combination therapies. Therefore, we investigated cell death pathways in vitro in human hepatoma, colon, renal, and lung cancer cells and in vivo in chorioallantoic membrane and xenograft models. Real-time cancer cell monitoring and cytokine profiling revealed a profoundly distinct response pattern to both drugs. 5-aza-dC induced p53-dependent tumor cell senescence and a high number of DNA double-strand breaks. In contrast, 5-aza-CR downregulated p53, induced caspase activation and apoptosis. These individual response patterns of tumor cells could be verified in vivo in chorioallantoic membrane assays and in a hepatoma xenograft model. Although 5-aza-CR and 5-aza-dC are viewed as drugs with similar therapeutic activity, they induce a diverse molecular response in tumor cells. These findings together with other reported differences enable and facilitate a rational design of new combination strategies to further exploit the epigenetic mode of action of these two drugs in different areas of clinical oncology. Mol Cancer Ther; 12(10); 2226-36. Ó2013 AACR.

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“…In cultured human embryonic lung fibroblasts, global hypomethylation occurs during both stress-induced and and replicative senescence. 42 A separate study found that passage number and genomic 5mC content were inversely correlated for hamster, human, and mice diploid fibroblasts. 43 In addition, treatment of human diploid fibroblasts with 5-azacytidine (5-azaC), a compound that inhibits methylation of cytosine in DNA, significantly reduces the doubling potential of cells in culture.…”

Section: Dna Hypomethylation and Hypermethylationmentioning

confidence: 97%

The Role of DNA Methylation in Aging, Rejuvenation, and Age-Related Disease

Johnson

Akman²,

Calimport³

et al. 2012

Rejuvenation Research

328

218

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DNA methylation is a major control program that modulates gene expression in a plethora of organisms. Gene silencing through methylation occurs through the activity of DNA methyltransferases, enzymes that transfer a methyl group from S-adenosyl-l-methionine to the carbon 5 position of cytosine. DNA methylation patterns are established by the de novo DNA methyltransferases (DNMTs) DNMT3A and DNMT3B and are subsequently maintained by DNMT1. Aging and age-related diseases include defined changes in 5-methylcytosine content and are generally characterized by genome-wide hypomethylation and promoter-specific hypermethylation. These changes in the epigenetic landscape represent potential disease biomarkers and are thought to contribute to age-related pathologies, such as cancer, osteoarthritis, and neurodegeneration. Some diseases, such as a hereditary form of sensory neuropathy accompanied by dementia, are directly caused by methylomic changes. Epigenetic modifications, however, are reversible and are therefore a prime target for therapeutic intervention. Numerous drugs that specifically target DNMTs are being tested in ongoing clinical trials for a variety of cancers, and data from finished trials demonstrate that some, such as 5-azacytidine, may even be superior to standard care. DNMTs, demethylases, and associated partners are dynamically shaping the methylome and demonstrate great promise with regard to rejuvenation.

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Comparison of global DNA methylation profiles in replicative versus premature senescence

Cited by 58 publications

References 17 publications

Senescence and p130/Rbl2: a new beginning to the end

Senescence and p130/Rbl2: a new beginning to the end

Differential Induction of Apoptosis and Senescence by the DNA Methyltransferase Inhibitors 5-Azacytidine and 5-Aza-2′-Deoxycytidine in Solid Tumor Cells

The Role of DNA Methylation in Aging, Rejuvenation, and Age-Related Disease

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