High levels of intracellular polyamines promote histone acetyltransferase activity resulting in chromatin hyperacetylation.
Polyamines stimulate expression of a variety of genes, including many implicated in cell proliferation. Indeed, aberrant expression of ornithine decarboxylase (ODC), a rate-limiting enzyme in polyamine biosynthesis, plays a causal role in tumorigenesis. Gene activity is influenced by dynamic changes in acetylation of nucleosomal histones. Although polyamines influence the histone acetyltransferase and deacetylase activities in cell-free systems, their ability to modulate these enzymes in live cells has never been established. To examine the effects of elevated intracellular levels of ODC and polyamines on gene transcription and histone acetylation, cells were infected with a retrovirus containing a cDNA for ODC. ODC overexpression potentiated the stimulatory effects of histone deacetylase inhibitors on reporter gene expression beyond that promoted by ODC or inhibitor treatment alone. Indeed, elevated intracellular levels of ODC promoted hyperacetylation of histones in several epidermal and fibroblast cell types. The ODC-mediated increase in acetylated histones was abrogated when cells were treated with alpha-difluoromethylornithine, a specific inhibitor of ODC activity, implying a distinct role for polyamines. Specifically, polyamines were found to enhance the action of histone acetyltransferases either directly or indirectly. Our studies document effects of elevated intracellular polyamine levels on histone acetylation in proliferating cells, suggesting a mechanism by which altered polyamine biosynthesis contributes to aberrant expression of genes, facilitating tumor growth. In addition, these studies may have implications for the development of drugs designed to regulate enzymes that modify the acetylation status of histones.
Hobbs
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CA
Lankenau Medical Research Center, Wynnewood, Pennsylvania 19096, USA. hobbsc@mlhs.org
Gilmour
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SK
D016475:3T3 Cells; D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism*; D000818:Animals; D002453:Cell Cycle; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017930:Genes, Reporter; D051548:Histone Acetyltransferases; D006877:Hydroxamic Acids / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009707:Nucleosomes / Q000378:metabolism; D009955:Ornithine Decarboxylase / Q000096:biosynthesis; D011073:Polyamines / Q000378:metabolism*; D020033:Protein Isoforms; D012190:Retroviridae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D014158:Transcription, Genetic
D002843:Chromatin; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D009707:Nucleosomes; D011073:Polyamines; D020033:Protein Isoforms; D029701:Saccharomyces cerevisiae Proteins; C012589:trichostatin A; D008156:Luciferases; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; D009955:Ornithine Decarboxylase