DNMT1 as a Molecular Target in a Multimodality-Resistant Phenotype in Tumor Cells

Mishra, Mark V.; Bisht, Kheem S.; Sun, Lunching; Muldoon-Jacobs, Kristi; Awwad, Rania T.; Kaushal, Aradhana; Nguyen, Phuongmai; Huang, Lei; Pennington, J. Daniel; Markovina, Stephanie; Bradbury, C. Matthew; Gius, David

doi:10.1158/1541-7786.mcr-07-0373

Cited by 38 publications

(28 citation statements)

References 35 publications

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“…The CAGE promoter contains binding sites for transcription factors such as ELK-1 and GATA-1, and ChIP assay showed binding of ELK-1 in SNU387 R cells and GATA-1 in Malme3M R cells, respectively (data not shown). Overexpression of DNMT1 was related with a multimodality-resistant phenotype in tumor cells (26), and moreover, overexpression of DNMT1 was seen in c-Fos-overexpressing tumor cells (26). In our study, we actually found a decreased expression of DNMT1 in SNU387 R and Malme3M R cells (Fig.…”

Section: Discussionsupporting

confidence: 68%

Cancer/Testis Antigen CAGE Exerts Negative Regulation on p53 Expression through HDAC2 and Confers Resistance to Anti-cancer Drugs

Kim

Park

et al. 2010

Journal of Biological Chemistry

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The role of the cancer/testis antigen CAGE in drug resistance was investigated. The drug-resistant human melanoma Malme3M (Malme3M R ) and the human hepatic cancer cell line SNU387 (SNU387 R ) showed in vivo drug resistance and CAGE induction. Induction of CAGE resulted from decreased expression and thereby displacement of DNA methyltransferase 1(DNMT1) from CAGE promoter sequences. Various drugs induce expression of CAGE by decreasing expression of DNMT1, and hypomethylation of CAGE was correlated with the increased expression of CAGE. Down-regulation of CAGE in these cell lines decreased invasion and enhanced drug sensitivity resulting from increased apoptosis. Down-regulation of CAGE also led to decreased anchorage-independent growth. Down-regulation of CAGE led to increased expression of p53, suggesting that CAGE may act as a negative regulator of p53. Down-regulation of p53 enhanced resistance to drugs and prevented drugs from exerting apoptotic effects. In SNU387 R cells, CAGE induced the interaction between histone deacetylase 2 (HDAC2) and Snail, which exerted a negative effect on p53 expression. Chromatin immunoprecipitation assay showed that CAGE, through interaction with HDAC2, exerted a negative effect on p53 expression in Malme3M R cells. These results suggest that CAGE confers drug resistance by regulating expression of p53 through HDAC2. Taken together, these results show the potential value of CAGE as a target for the development of cancer therapeutics.

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Section: Discussionsupporting

confidence: 68%

Cancer/Testis Antigen CAGE Exerts Negative Regulation on p53 Expression through HDAC2 and Confers Resistance to Anti-cancer Drugs

Kim

Park

et al. 2010

Journal of Biological Chemistry

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“…Therefore, new therapeutic options are urgently needed. Epigenetic silencing of gene expression, especially that mediated by promoter hypermethylation, plays an important role in the development and progression of PCa, as well as in the emergence of resistance to chemotherapy [17,18]. Thus, DNMTs might constitute a valuable therapeutic target for PCa treatment.…”

Section: Discussionmentioning

confidence: 99%

Anti-Tumoral Effect of the Non-Nucleoside DNMT Inhibitor RG108 in Human Prostate Cancer Cells

Graça¹,

Sousa²,

Baptista³

et al. 2014

CPD

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Background: Current therapeutic strategies for advanced prostate cancer (PCa) are largely ineffective. Because aberrant DNA methylation associated with inappropriate gene-silencing is a common feature of PCa, DNA methylation inhibitors might constitute an alternative therapy. In this study we aimed to evaluate the anti-cancer properties of RG108, a novel non-nucleoside inhibitor of DNA methyltransferases (DNMT), in PCa cell lines. Methods:The anti-tumoral impact of RG108 in LNCaP, 22Rv1, DU145 and PC-3 cell lines was assessed through standard cell viability, apoptosis and cell cycle assays. Likewise, DNMT activity, DNMT1 expression and global levels of DNA methylation were evaluated in the same cell lines. The effectiveness of DNA demethylation was further assessed through the determination of promoter methylation and transcript levels of GSTP1, APC and RAR-/J2, by quantitative methylation-specific PCR and RT-PCR, respectively.Results: RG108 led to a significant dose and time dependent growth inhibition and apoptosis induction in LNCaP, 22Rv1 and DU145. LNCaP and 22Rv1 also displayed decreased DNMT activity, DNMT1 expression and global DNA methylation. Interestingly, chronic treatment with RG108 significantly decreased GSTP1, APC and RAR-/J2 promoter hypermethylation levels, although mRNA reexpression was only attained GSTP1 and APC.Conclusions: RG108 is an effective tumor growth suppressor in most PCa cell lines tested. This effect is likely mediated by reversion of aberrant DNA methylation affecting cancer related-genes epigenetically silenced in PCa. However, additional mechanism might underlie the anti-tumor effects of RG108. In vivo studies are now mandatory to confirm these promising results and evaluate the potential of this compound for PCa therapy.

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“…We similarly observed that oxidized LDL downregulates KLF2 expression in endothelial cells ( Figure VII in the online-only Data Supplement), but did not probe the molecular mechanisms responsible for this downregulation. It is noteworthy that DNMTs are impacted by the oxidative milieu, 38 and that oxidized LDL could, thus, affect gene expression via oxidative stress. However, oxidative stress is unlikely to be responsible for the effect of native LDL because p66shc, a master regulator of the cellular redox environment, does not mediate LDL-induced repression of KLF2 ( Figure II in the online-only Data Supplement).…”

Section: Silencing Of Endothelial Klf2 By Ldl 1941mentioning

confidence: 99%

Histone and DNA Methylation–Mediated Epigenetic Downregulation of Endothelial Kruppel-Like Factor 2 by Low-Density Lipoprotein Cholesterol

Kumar

Vikram

et al. 2013

ATVB

114

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Objective-Low-density lipoprotein (LDL) cholesterol induces endothelial dysfunction and is a major modifiable risk factor for coronary heart disease. Endothelial Kruppel-like Factor 2 (KLF2) is a transcription factor that is vital to endotheliumdependent vascular homeostasis. The purpose of this study is to determine whether and how LDL affects endothelial KLF2 expression. Approach and Results-LDL downregulates KLF2 expression and promoter activity in endothelial cells. LDL-induced decrease in KLF2 parallels changes in endothelial KLF2 target genes thrombomodulin, endothelial NO synthase, and plasminogen activator inhibitor-1. Pharmacological inhibition of DNA methyltransferases or knockdown of DNA methyltransferase 1 prevents downregulation of endothelial KLF2 by LDL. LDL induces endothelial DNA methyltransferase 1 expression and DNA methyltransferase activity. LDL stimulates binding of the DNA methylCpG-binding protein-2 and histone methyltransferase enhancer of zeste homolog 2, whereas decreases binding of the KLF2 transcriptional activator myocyte enhancing factor-2, to the KLF2 promoter in endothelial cells. Knockdown of myocyte enhancing factor-2, or mutation of the myocyte enhancing factor-2 site in the KLF2 promoter, abrogates LDLinduced downregulation of endothelial KLF2 and thrombomodulin, and KLF2 promoter activity. Similarly, knockdown of enhancer of zeste homolog 2 negates LDL-induced downregulation of KLF2 and thrombomodulin in endothelial cells. for myocyte enhancing factor-2 (MEF2), a transcription factor which upregulates KLF2, 9,10,15 and the tumor suppressing transcription factor p53 which downregulates KLF2. 16 Although studies on epigenetic modulation of KLF2 expression are limited, emerging evidence suggests that histone modifiers, such as the histone methyltransferase enhancer of zeste homolog 2 (EZH2), the catalytic subunit of Polycomb repressive complex 2 which is implicated in tumorigenesis and is responsible for trimethylation of Histone 3 on lysine 27, play an important part in governing KLF2 expression. 17Cholesterol-rich lipid particles and hypercholesterolemia are associated with epigenetic changes in vitro and in experimental animal models as well as in humans. ApoE −/− mice fed a high-fat diet have aberrant DNA methylation patterns, including decreased global methylation in aorta and peripheral blood mononuclear cells, 18 and human atherosclerotic tissue samples display genomic hypomethylation.19 P66shc is one of the genes epigenetically modified by cholesterolrich proatherogenic particles, such as LDL.20 P66shc mediates endothelial oxidative stress and fatty streak formation in hypercholesterolemic mice. 21 However, p66shc is only one of many genes whose epigenetic modification by hypercholesterolemia may contribute to the development of vascular disease. Intrigued by the possibility that endothelial KLF2 might also be epigenetically regulated in a hypercholesterolemic environment, we asked whether LDL cholesterol changes endothelial KLF2 transcription, and investigated the rol...

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DNMT1 as a Molecular Target in a Multimodality-Resistant Phenotype in Tumor Cells

Cited by 38 publications

References 35 publications

Cancer/Testis Antigen CAGE Exerts Negative Regulation on p53 Expression through HDAC2 and Confers Resistance to Anti-cancer Drugs

Cancer/Testis Antigen CAGE Exerts Negative Regulation on p53 Expression through HDAC2 and Confers Resistance to Anti-cancer Drugs

Anti-Tumoral Effect of the Non-Nucleoside DNMT Inhibitor RG108 in Human Prostate Cancer Cells

Histone and DNA Methylation–Mediated Epigenetic Downregulation of Endothelial Kruppel-Like Factor 2 by Low-Density Lipoprotein Cholesterol

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