DNA methyltransferases and their roles in tumorigenesis

Wu, Zhen; Xu, Jie

doi:10.1186/s40364-017-0081-z

Cited by 295 publications

(185 citation statements)

References 78 publications

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“…4 The DNMTs (DNMT1, DNMT3A, and DNMT3B) aberrant expression has been associated with almost all forms of tumorigenesis in human. 5 As a result, increased the occurrence of CGI hypermethylation mainly in the TSGs, eg, the promoter of p16 (CDKN2A), is observed, which renders them transcriptionally inactive. 4 The reversibility of DNA hypermethylation, therefore, has drawn attention from last decade, leading to the development of DNMT inhibitors (DNMTi) as epigenetic therapeutics.…”

mentioning

confidence: 99%

Curcumin‐mediated demethylation of the proximal promoter CpG island enhances the KLF4 recruitment that leads to increased expression of p21Cip1 in vitro

Chatterjee

Ghosh

Kanade

2018

J of Cellular Biochemistry

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Curcumin, the active component of the spice turmeric, induce global DNA hypomethylation as it has been shown to inhibit DNA methyltransferases. It promotes cell death in cancer cells by arresting in the G1 phase. It was explained to cause increased expression of cell cycle regulator, p21 (WAF1/Cip1); however, the mechanism remains not clear. The p21 promoter harvests a CpG island (CGI) in the proximal region enriched with CG dinucleotide clusters with Kruppel-like factor 4 (KLF4) transcription factor binding site. We probed the p21 promoter CGI (spanning from -135 to +12, respective to the transcription start site) to detect alterations in cytosine methylation level in response to curcumin exposure in four different human cancer cell lines: A431, A549, MCF7, and HeLa. We observed curcumin (20 µM) treatment significantly increased the expression of p21, and the promoter CGI was demethylated in a dose-dependent manner. The curcumin significantly raised the level KLF4 and enhanced the p21 promoter occupancy by KLF4. From our results we hypothesize that curcumin-mediated demethylation of the p21 proximal promoter and increased KLF4 expression as well as its binding to its proximal promoter could serve as a mechanism that could be hypothesized to cause upregulation of p21 in presence of curcumin and thus its therapeutic implications could further be investigated.

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confidence: 99%

Curcumin‐mediated demethylation of the proximal promoter CpG island enhances the KLF4 recruitment that leads to increased expression of p21Cip1 in vitro

Chatterjee

Ghosh

Kanade

2018

J of Cellular Biochemistry

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“…This could explain how the p16Ink4a levels observed in N-WASP ko keratincoytes in vivo are particularly inhibiting DMBA/TPA-induced tumor formation, where Hras1 appears to be the primary target for the initiation stage (30). DNMT1 overexpression correlates with bad prognosis in different cancers (31) and knockdown of DNMT1 in esophageal squamous cell cancer cell lines dramatically inhibited their self-renewal (32), suggesting that the reduction of DNMT1 could contribute to reduced tumor formation.…”

Section: Discussionmentioning

confidence: 99%

Negative Regulation of p53-Induced Senescence by N-WASP Is Crucial for DMBA/TPA-Induced Skin Tumor Formation

Petersen

Mariscal

et al. 2019

Cancer Research

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Mice with a keratinocyte-restricted deletion of the actin polymerization-promoting molecule, N-WASP, display cyclic hair loss and skin inflammation. Here, we showed that these mice were also resistant to 7,12-dimethylbenz(a) anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin tumor formation. This resistance correlated with decreased expression of the senescence regulator, DNMT1, and increased expression of the senescence marker, p16Ink4a, in N-WASP-deficient epidermis. Moreover, primary N-WASP-null keratinocytes displayed a premature senescence phenotype in vitro. Expression and activation of p53, a major inducer of senescence, was not significantly altered in N-WASP-null keratinocytes. However, impairment of p53 function effectively rescued the senescence phenotype, indicating that N-WASP was an inhibitor of p53-induced senescence. Mechanistically, N-WASP regulated senescence by preventing p53-dependent degradation of the H3K9 methyltransferases, G9a/GLP, and the DNA methyltransferase, DNMT1, which both control keratinocyte senescence. This pathway collaborated with other N-WASP-independent, senescence-promoting signaling downstream of p53 and allowed the fine tuning of p53induced senescence by N-WASP. Collectively, these data reveal N-WASP as an inhibitor of p53-induced senescence, which might be of importance for skin tumor formation and cellular aging of keratinocytes.Significance: These findings demonstrate that N-WASP regulates p53-dependent senescence in keratinocytes in vitro and in vivo. Gene expression analysisRNA from skin and keratinocytes culture was prepared using the GeneElute Mammalian Total RNA Miniprep Kit (RNT350, Sigma) according to the instructions of the manufacturer. Skin Li et al.

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“…Global epigenetic alterations in malignant cells are the consequence of dysregulated DNMT expression (including mutations in DNMT coding genes), and clonal selection of cellular populations with aberrant methylation. Hypermethylation profile is unique for each type of tumor, in which inactivation of certain genes may cause proliferative advantage and clonal selection (ZHANG, et al 2017).…”

Section: Epigenetic Modifications In Malignancymentioning

confidence: 99%

Epigenetics in disease etiopathogenesis

Glavaški

Stankov

2019

Genetika

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2019): Epigenetics in disease etiopathogenesis.-Genetika, Vol 51, No.3, 975-994. The term epigenetics refers to heritable changes in gene expression that are not caused by modifications in DNA sequence. Epigenetic changes are DNA methylation, histone modifications, nucleosome positioning, and non-coding RNA (including microRNA) mediated modifications. Epigenetic mechanisms are involved in malignant diseases, imprinting defects, and some hereditary diseases. Recent research explained the role of epigenetic disorders in infections, autoimmune, neurodegenerative and bone diseases, as well as in psoriasis, endometriosis, and polycystic ovary syndrome. Epigenetic modifications have a potential clinical application as diagnostic and prognostic biomarkers, and also as therapeutic targets in oncology, endocrinology, cardiology, and neuropsychiatry. Stress, anxiety, depression, emotions and many other psychological factors may affect epigenetic mechanisms. Influence of preconception parental stress exposure transmits to the next generation through epigenetic changes, as direct results of prenatal and postnatal environmental factors. Epigenetic changes identify environmental factors which affect health and cause disease onset. Milk is the sophisticated system of communication between mother and infant, operating via epigenetic mechanisms. Lifelong consumption of bovine milk causes epigenetic disorders. Recent studies provide important information about the role of bioactive dietary nutrients which modify DE SARIO, A. (2009): Clinical and molecular overview of inherited disorders resulting from epigenomic dysregulation. Eur. J. Med. Genet., 52(6): 363-372.

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DNA methyltransferases and their roles in tumorigenesis

Cited by 295 publications

References 78 publications

Curcumin‐mediated demethylation of the proximal promoter CpG island enhances the KLF4 recruitment that leads to increased expression of p21Cip1 in vitro

Curcumin‐mediated demethylation of the proximal promoter CpG island enhances the KLF4 recruitment that leads to increased expression of p21Cip1 in vitro

Negative Regulation of p53-Induced Senescence by N-WASP Is Crucial for DMBA/TPA-Induced Skin Tumor Formation

Epigenetics in disease etiopathogenesis

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