title: The epigenetic drug 5-azacytidine interferes with cholesterol and lipid metabolism.
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.
authors.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.
authors.forename: Steve
authors.initials: S
authors.lastname: Poirier
authors.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.
authors.forename: Samaneh
authors.initials: S
authors.lastname: Samami
authors.affiliation: From the Laboratory of Molecular Cell Biology, Montreal Heart Institute, Montréal, Québec H1T 1C8, Canada.
authors.forename: Maya
authors.initials: M
authors.lastname: Mamarbachi
authors.affiliation: From the Laboratory of Molecular Cell Biology, Montreal Heart Institute, Montréal, Québec H1T 1C8, Canada.
authors.forename: Annie
authors.initials: A
authors.lastname: Demers
authors.affiliation: the Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755-1404.
authors.forename: Ta Yuan
authors.initials: TY
authors.lastname: Chang
authors.affiliation: the Department of Biochemistry and Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Vance
authors.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.
authors.forename: Grant M
authors.initials: GM
authors.lastname: Hatch
authors.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.
authors.forename: Gaétan
authors.initials: G
authors.lastname: Mayer
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D006224:Cricetinae; D019175:DNA Methylation / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000187:drug effects*; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D011743:Pyrimidines / Q000096:biosynthesis; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics
chemical_list: D011743:Pyrimidines; C497390:SREBF2 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; D002784:Cholesterol; C030986:pyrimidine; D001374:Azacitidine
keywords: CTP; Cholesterol Metabolism; DNA Methylation; Enzyme Inhibitor; Glycerolipid; Lipid Droplets; Pyrimidine; Sterol Regulatory Element-binding Proteins (SREBPs); UMP Synthase; de Novo Pyrimidine Synthesis