Induction of gene expression by 5-Aza-2′-deoxycytidine in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) but not epithelial cells by DNA-methylation-dependent and -independent mechanisms

Schmelz, Karin; Sattler, Nicole; Wagner, Mandy; Lübbert, Michael; Dörken, Bernd; Tamm, Ingo

doi:10.1038/sj.leu.2403552

Cited by 115 publications

(94 citation statements)

References 34 publications

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“…6). Similar DNA methylationindependent gene inactivation, which can be activated by 5-Aza CdR, was reported in mouse centromeric heterochromatin (Takebayashi et al, 2001) and acute myeloid leukemia cells (Schmelz, Sattler, Wagner, Lubbert, Dorken, & Tamm, 2005). Treatment of CHO cells with both agents shows only an additive effect on the increase of the amounts of acetylated histone H3.…”

Section: Discussionsupporting

confidence: 72%

Cell type-specific activation of the cytomegalovirus promoter by dimethylsulfoxide and 5-Aza-2'-deoxycytidine

Radhakrishnan¹,

Basma²,

Klinkebiel³

et al. 2008

The International Journal of Biochemistry & Cell Biology

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The cytomegalovirus promoter is a very potent promoter commonly used for driving the expression of transgenes, though it gradually becomes silenced in stably transfected cells. We examined the methylation status of the cytomegalovirus promoter in two different cell lines and characterized its mechanisms of activation by dimethylsulfoxide and 5-Aza-2′-deoxycytidine. The cytomegalovirus promoter stably transfected into Chinese hamster ovary cells is suppressed by DNA methylation-independent mechanisms, which is different from the rat embryonic cardiomyoblast H9c2-Fluc.3 cells in which the cytomegalovirus promoter is silenced by methylation. Dimethylsulfoxide and 5-Aza-2′-deoxycytidine can activate the cytomegalovirus promoter in both cell types by overlapping mechanisms. Dimethylsulfoxide activates the cytomegalovirus promoter in Chinese hamster ovary cells by promoting histone acetylation and the activation of p38 mitogen-activated protein kinase and nuclear factor κB signaling pathways, while 5-Aza-2′-deoxycytidine increases histone acetylation and activates the nuclear factor κB but not the p38 mitogen-activated protein kinase pathway. In H9c2-Fluc.3 cells, both agents promote demethylation of the cytomegalovirus promoter, and enhance its activity exclusively through activation of the nuclear factor κB pathway and to a lesser extent of the p38 mitogen-activated protein kinase pathway. Our findings suggest that suppression and activation of the cytomegalovirus promoter are cell type-specific. These results may be used for developing strategies to enhance the expression of transgenes and the production of recombinant proteins encoded by transgenes controlled by a cytomegalovirus promoter.

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Section: Discussionsupporting

confidence: 72%

Cell type-specific activation of the cytomegalovirus promoter by dimethylsulfoxide and 5-Aza-2'-deoxycytidine

Radhakrishnan¹,

Basma²,

Klinkebiel³

et al. 2008

The International Journal of Biochemistry & Cell Biology

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“…Surprisingly, the administration of 5AC alone was associated with induction of acetylated histones H3 and H4 in 11/23 evaluable patients. Coupled with recent studies suggesting that DAC can induce expression of unmethylated genes such as CDKN2D and p21 WAF1/CIP1 (Zhu et al, 2001;Schmelz et al, 2005a), these data indicate that molecular mechanisms in addition to the reexpression of methylated genes may contribute to the clinical activity of DNMT inhibitors. This study examines the induction of the expression of the unmethylated cell cycle regulatory gene p21 WAF1/CIP1 (Brakensiek et al, 2005;Scott et al, 2006) in response to the DNMT inhibitor DAC.…”

Section: Introductionsupporting

confidence: 63%

“…In this study, we observed a synergistic upregulation of p21 WAF1/CIP1 by DAC and HDAC inhibitors despite the unmethylated status of its promoter. Recent studies indicated that decitabine (DAC) can induce regional chromatin remodeling of other unmethylated genes, including RPGR, CD14, PTPN22 and calgranulin, which could explain the above-mentioned synergy (Schmelz et al, 2005a). However, the synergistic interaction between DNMT and HDAC inhibitors may stem from other potentially non-epigenetic mechanisms in addition to the inhibition of HDAC recruited directly by methyl-binding proteins to methylated promoters (Bird and Wolffe, 1999).…”

Section: Discussionmentioning

confidence: 99%

p21WAF1/CIP1 induction by 5-azacytosine nucleosides requires DNA damage

et al. 2008

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Decitabine (DAC) and 5-azacitidine have recently been approved for the treatment of myelodysplastic syndrome. The pharmacodynamic effects of DAC and 5-azacitidine outside their known activity as inhibitors of DNA methyltransferases (DNMTs) require further investigation. The purpose of this study was to investigate the effect of DAC on the expression of p21 WAF1/CIP1 , a gene with a putative CpG island surrounding its promoter region. Promoter methylation analysis of p21 WAF1/CIP1 in leukemia cells revealed the absence of CpG methylation. However, DAC upregulated p21 WAF1/CIP1 expression in a dosedependent manner (ED 50 ¼ 103.34 nM) and induced G2/M cell cycle arrest in leukemia cells. Sequential application of DAC followed by different histone deacetylase inhibitors induced expression of p21 WAF1/CIP1 synergistically. Upregulation of p21 WAF1/CIP1 paralleled DAC-induced apoptosis (ED 50 ¼ 153 nM). Low doses of DAC induced c-H2AX expression (ED 50 ¼ 16.5 nM) and upregulated p21 WAF1/CIP1 in congenic HCT 116 colon cancer cells in a DNMT-independent and p53-dependent fashion. Inhibition of p53 transactivation by pifithrin-a or the kinase activity of ATM by either the specific ATM inhibitor KU-5593 or caffeine abrogated p21 WAF1/CIP1 upregulation, indicating that DAC upregulation of p21 WAF1/CIP1 was p53-and ATM-dependent in leukemia cells. In conclusion, DAC upregulates p21 WAF1/CIP1 in DNMT-independent manner via the DNA damage/ATM/ p53 axis.

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“…ICAM-1 can be reactivated by both DAC and TSA alone, through increasing ICAM-1 promoter histone H3 acetylation and H3 Lys 4 methylation. Increased histone acetylation, H3 Lys 4 methylation, and/or gene expression by DNMT inhibitors independently of effects on DNA methylation have been described before (38)(39)(40). The potency of the DNMT inhibitors DAC and zebularine to reactivate ICAM-1 independently of promoter DNA methylation indicates that methylation-independent silencing activity of DNMTs might be essential for ICAM-1 down-regulation in tumor endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Regulation of Tumor Endothelial Cell Anergy: Silencing of Intercellular Adhesion Molecule-1 by Histone Modifications

Hellebrekers

Castermans

Viré³

et al. 2006

Cancer Research

142

107

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Tumors can escape from immunity by repressing leukocyte adhesion molecule expression on tumor endothelial cells and by rendering endothelial cells unresponsive to inflammatory activation. This endothelial cell anergy is induced by angiogenic growth factors and results in reduced leukocytevessel wall interactions, thereby attenuating infiltration of leukocytes into the tumor. This report describes a novel mechanism of endothelial cell anergy regulation. We recently reported that DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors have angiostatic activity. Here, we studied whether epigenetic mechanisms regulate this angiogenesis-mediated escape from immunity. We found that DNMT inhibitors 5-aza-2 ¶-deoxycytidine and zebularine, as well as HDAC inhibitor trichostatin A, reexpressed intercellular adhesion molecule-1 (ICAM-1) on tumor-conditioned endothelial cells in vitro , resulting in restored leukocyte-endothelial cell adhesion. In addition, treatment with DNMT or HDAC inhibitors in vivo also restored ICAM-1 expression on tumor endothelial cells from two different mouse tumor models. Furthermore, leukocyte-vessel wall interactions in mouse tumors were increased by these compounds, as measured by intravital microscopy, resulting in enhanced leukocyte infiltration. We show that ICAM-1 down-regulation in tumor endothelial cells is associated with ICAM-1 promoter histone H3 deacetylation and loss of histone H3 Lys 4 methylation but not with DNA hypermethylation. In conclusion, our data show that ICAM-1 is epigenetically silenced in tumor endothelial cells by promoter histone modifications, which can be overcome by DNMT and HDAC inhibitors, suggesting a new molecular mechanism based on which novel therapeutic approaches for cancer can be

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Induction of gene expression by 5-Aza-2′-deoxycytidine in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) but not epithelial cells by DNA-methylation-dependent and -independent mechanisms

Cited by 115 publications

References 34 publications

Cell type-specific activation of the cytomegalovirus promoter by dimethylsulfoxide and 5-Aza-2'-deoxycytidine

Cell type-specific activation of the cytomegalovirus promoter by dimethylsulfoxide and 5-Aza-2'-deoxycytidine

p21WAF1/CIP1 induction by 5-azacytosine nucleosides requires DNA damage

Epigenetic Regulation of Tumor Endothelial Cell Anergy: Silencing of Intercellular Adhesion Molecule-1 by Histone Modifications

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