Hypomethylation: One Side of a Larger Picture

Dunn, Barbara K.

doi:10.1111/j.1749-6632.2003.tb05960.x

Cited by 146 publications

(104 citation statements)

References 109 publications

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“…This phenomena is also not well understood, but may contribute to carcinogenesis by several mechanisms, such as loss of imprinting, chromosomal instability, and reactivation of transposable elements (reviewed in Esteller, 2003). Due to limited space, we are not able to give a more detailed overview about this topic, and we encourage interested readers to refer to other excellent reviews on the connection of DNA methylation and cancer (Dunn, 2003;Jaenisch and Bird, 2003;Laird, 2003;Szyf, 2003).…”

Section: Aberrant Gene Repression and Cancermentioning

confidence: 99%

Linking the epigenetic ‘language’ of covalent histone modifications to cancer

2004

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Covalent modifications of histones, such as acetylation, methylation, and phosphorylation, and other epigenetic modulations of the chromatin, such as methylation of DNA and ATP-dependent chromatin reorganisation, can play a major part in the multistep process of carcinogenesis, with far-reaching implications for human biology and human health. This review focuses on how aberrant covalent histone modifications may contribute to the development of a variety of human cancers, and discusses the recent findings with regard to potential therapies.

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Section: Aberrant Gene Repression and Cancermentioning

confidence: 99%

Linking the epigenetic ‘language’ of covalent histone modifications to cancer

2004

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“…Hypomethylation is involved in the progression from the premalignant to a fully developed malignancy (17) and leads to activation of genes important for cancer development. Studies have indicated that overexpression of maspin in gastric, pancreatic, and ovarian cancers results from promoter CpG demethylation (refs.…”

Section: Maspin Gene Regulation Dna Methylation and Histone Methylamentioning

confidence: 99%

Maspin: The New Frontier

Khalkhali‐Ellis

2006

Clinical Cancer Research

113

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Maspin (mammary serine protease inhibitor) was identified in 1994 by subtractive hybridization analysis of normal mammary tissue and breast cancer cell lines. Subsequently, emerging evidence portrays maspin as a multifaceted protein, interacting with diverse group of intercellular and extracellular proteins, regulating cell adhesion, motility, apoptosis, and angiogenesis and critically involved in mammary gland development. The tissue-specific expression of maspin is epigenetically controlled, and aberrant methylation of maspin promoter is closely associated with maspin gene silencing. Identification of new tissue sites expressing maspin and novel maspin-binding partners has expanded the horizon for maspin research and promises maspin-based therapeutic approaches for combating cancer. This perspective briefly outlines the past and present strides in deciphering this unique molecule and speculates on new frontiers in maspin research and prospects of maspin as a diagnostic/prognostic indicator in cancer.The serine protease inhibitor superfamily (serpins) is categorized to inhibitory and noninhibitory serpins (1). Inhibitory serpins use their reactive center loop to trap the target proteinase and inhibit its activity (1). The noninhibitory serpins have shorter NH 2 and COOH termini, and they also lack the classic serpin secretory signal peptide (1). Recent studies indicate serpins function beyond their serpin properties: they are involved in cell adhesion and play a role in extracellular matrix remodeling (2).Maspin (mammary serine protease inhibitor) shares sequence homology with inhibitory serpins, such as plasminogen activator inhibitors 1 and 2, a-1 anti-trypsin, and noninhibitory serpin ovalbumin (3), and several recent sequence comparisons seem to suggest that maspin is more closely related to noninhibitory clade B serpins. The reactive center loop of maspin is significantly shorter than that of most inhibitory serpins, and maspin does not undergo conformational rearrangement required to inactivate target protease(s) (4). However, the reactive center loop of maspin is clearly important for its function; studies using synthetic maspin reactive center loop peptides and maspin/ovalbumin chimeras reveal that this region is important for promoting cell adhesion (5).In the past decade, with the expansion of studies on maspin, novel protein-binding partners have been identified and provided insight into the molecular aspects of its regulation and its divergent mechanism of action. More importantly, they have presented new prospects for therapeutic interventions for breast, prostate, and many other cancers.

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“…[12][13][14][15][16][17] Hence remethylation of DNA by condensing the chromatin could prevent or decrease the accessibility of transcription machinery to the DNA, resulting in a decrease in mRNA expression. In support of this conjecture, targretin has been reported to decrease the expression of many more genes than it increased in lung tumors.…”

Section: Discussionmentioning

confidence: 99%

Modulation by budesonide of DNA methylation and mRNA expression in mouse lung tumors

Pereira

Tao

Liu

et al. 2006

Intl Journal of Cancer

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Biomarkers are being developed that can aid in the evaluation of cancer therapeutic and chemopreventive drugs. Two suggested biomarkers found in mouse lung tumors are DNA hypomethylation and alterations in mRNA expression of genes, such as 18S RNA, caspase 3, cyclin B2, cyclin E1, iNOS and survivin. Budesonide is very efficacious in preventing lung tumors in mice, so that its ability to modulate biomarkers in lung tumors was determined. Lung tumors were induced by vinyl carbamate in female strain A/J mice. Budesonide (2.0 mg/kg diet) was administered for 2, 7 and 21 days or for 14 days followed by a 7-days' holding period prior to the killing of the mice at week 27. After 2 days of budesonide treatment, the size of the lung tumors was reduced. Tumor size continued to decrease during the 21 days of treatment. In the tumors, 2 days of treatment resulted in (i) increased methylation of DNA, reversing DNA hypomethylation, (ii) increased expression of 18S RNA and (iii) decreased mRNA expression of caspase 3, cyclin B2, cyclin E1, iNOS and survivin. Termination of budesonide treatment at 7 days prior to killing did not affect the size of the tumors, but did result in increased mRNA expression of the 5 genes, approaching the expression level in tumors from control mice. Hence, budesonide rapidly decreased the size of lung tumors, reversed DNA hypomethylation and modulated mRNA expression of genes; with the molecular alterations requiring continued treatment with the drug for maintenance. ' 2006 Wiley-Liss, Inc.Key words: budesonide; biomarkers; chemoprevention; DNA hypomethylation; lung cancer; mRNA expression; mouse lung tumors The development of cancer chemopreventive and therapeutic agents would be aided by the use of biomarkers. Biomarkers have the advantage of requiring a shorter duration of treatment than either the prevention or regression of tumors. In clinical trials, the greatest utility of biomarkers appears to be in studies that determine their modulation by relatively short-term treatment with therapeutic and chemopreventive agents. Recent advances in the molecular biology of cancer have suggested several biological and molecular endpoints that might be useful as biomarkers, including DNA hypomethylation and alteration in mRNA expression of cancer-related genes.Budesonide, a synthetic anti-inflammatory glucocorticoid used to control mild-to-moderate persistent asthma, 1 has been shown to prevent the formation of lung adenomas and adenocarcinomas in mice when administered either by inhalation or in the diet. 2-7 As a chemopreventive agent, budesonide appears to decrease both the growth rate of tumors and the progression of adenomas to adenocarcinomas. 4 Lung tumors from budesonide-treated mice were smaller and contained fewer carcinomas when compared with tumors from mice that were not administered the drug. Budesonide has also been demonstrated to prevent the occurrence of DNA hypomethylation in mouse lung tumors 4,5 and to modulate the mRNA expression of cancer-related genes. 4,8 Another drug that is eff...

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Hypomethylation: One Side of a Larger Picture

Cited by 146 publications

References 109 publications

Linking the epigenetic ‘language’ of covalent histone modifications to cancer

Linking the epigenetic ‘language’ of covalent histone modifications to cancer

Maspin: The New Frontier

Modulation by budesonide of DNA methylation and mRNA expression in mouse lung tumors

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