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The epigenetic drug 5-azacytidine interferes with cholesterol and lipid metabolism.
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The epigenetic drug 5-azacytidine interferes with cholesterol and lipid metabolism.

Author: S Poirier Affiliation: From the Laboratory of Molecular Cell Biology, Montreal Heart Institute, Montréal, Québec H1T 1C8, Canada, the Département de Pharmacologie, Faculté de Médecine, Université de Montréal, Montréal, Québec H3C 3J7, Canada.S Samami Affiliation: From the Laboratory of Molecular Cell Biology, Montreal Heart Institute, Montréal, Québec H1T 1C8, Canada, the Département de Pharmacologie, Faculté de Médecine, Université de Montréal, Montréal, Québec H3C 3J7, Canada.M Mamarbachi Affiliation: From the Laboratory of Molecular Cell Biology, Montreal Heart Institute, Montréal, Québec H1T 1C8, Canada.A Demers Affiliation: From the Laboratory of Molecular Cell Biology, Montreal Heart Institute, Montréal, Québec H1T 1C8, Canada.TY Chang Affiliation: the Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755-1404.All authors
Edition/Format: Article Article : English
Publication:The Journal of biological chemistry, 2014 Jul 04; 289(27): 18736-51
Summary:
DNA methylation and histone acetylation inhibitors are widely used to study the role of epigenetic marks in the regulation of gene expression. In addition, several of these molecules are being tested in clinical trials or already in use in the clinic. Antimetabolites, such as the DNA-hypomethylating agent 5-azacytidine (5-AzaC), have been shown to lower malignant progression to acute myeloid leukemia and to prolong  Read more...
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Document Type: Article
All Authors / Contributors: S Poirier Affiliation: From the Laboratory of Molecular Cell Biology, Montreal Heart Institute, Montréal, Québec H1T 1C8, Canada, the Département de Pharmacologie, Faculté de Médecine, Université de Montréal, Montréal, Québec H3C 3J7, Canada.; S Samami Affiliation: From the Laboratory of Molecular Cell Biology, Montreal Heart Institute, Montréal, Québec H1T 1C8, Canada, the Département de Pharmacologie, Faculté de Médecine, Université de Montréal, Montréal, Québec H3C 3J7, Canada.; M Mamarbachi Affiliation: From the Laboratory of Molecular Cell Biology, Montreal Heart Institute, Montréal, Québec H1T 1C8, Canada.; A Demers Affiliation: From the Laboratory of Molecular Cell Biology, Montreal Heart Institute, Montréal, Québec H1T 1C8, Canada.; TY Chang Affiliation: the Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755-1404.; DE Vance Affiliation: the Department of Biochemistry and Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.; GM Hatch Affiliation: the DREAM Theme, Manitoba Institute of Child Health, Departments of Pharmacology and Therapeutics and Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba R3E 0T6, Canada, and.; G Mayer Affiliation: From the Laboratory of Molecular Cell Biology, Montreal Heart Institute, Montréal, Québec H1T 1C8, Canada, the Département de Pharmacologie, Faculté de Médecine, Université de Montréal, Montréal, Québec H3C 3J7, Canada, the Département de Médecine, Faculté de Médecine, Université de Montréal, Montréal, Québec H3C 3J7, Canada gaetan.mayer@icm-mhi.org.
ISSN:0021-9258
Language Note: English
Unique Identifier: 5608119582
Awards:

Abstract:

DNA methylation and histone acetylation inhibitors are widely used to study the role of epigenetic marks in the regulation of gene expression. In addition, several of these molecules are being tested in clinical trials or already in use in the clinic. Antimetabolites, such as the DNA-hypomethylating agent 5-azacytidine (5-AzaC), have been shown to lower malignant progression to acute myeloid leukemia and to prolong survival in patients with myelodysplastic syndromes. Here we examined the effects of DNA methylation inhibitors on the expression of lipid biosynthetic and uptake genes. Our data demonstrate that, independently of DNA methylation, 5-AzaC selectively and very potently reduces expression of key genes involved in cholesterol and lipid metabolism (e.g. PCSK9, HMGCR, and FASN) in all tested cell lines and in vivo in mouse liver. Treatment with 5-AzaC disturbed subcellular cholesterol homeostasis, thereby impeding activation of sterol regulatory element-binding proteins (key regulators of lipid metabolism). Through inhibition of UMP synthase, 5-AzaC also strongly induced expression of 1-acylglycerol-3-phosphate O-acyltransferase 9 (AGPAT9) and promoted triacylglycerol synthesis and cytosolic lipid droplet formation. Remarkably, complete reversal was obtained by the co-addition of either UMP or cytidine. Therefore, this study provides the first evidence that inhibition of the de novo pyrimidine synthesis by 5-AzaC disturbs cholesterol and lipid homeostasis, probably through the glycerolipid biosynthesis pathway, which may contribute mechanistically to its beneficial cytostatic properties.

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