title: Trichostatin A induces 5-lipoxygenase promoter activity and mRNA expression via inhibition of histone deacetylase 2 and 3.
abstract: The 5-lipoxygenase (5-LO) is the key enzyme in the formation of leukotrienes. We have previously shown that the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) activates 5-LO transcription via recruitment of Sp1, Sp3 and RNA polymerase II to the proximal promoter. To identify the HDACs involved in the regulation of 5-LO promoter activity isoform-specific HDAC inhibitors were applied. 5-LO promoter activity and mRNA expression were up-regulated by the class I HDAC inhibitors apicidin and MS-275 but not by class II inhibitors. Knockdown of HDAC 1, 2 and 3 revealed that HDAC2 and HDAC3 but not HDAC1 is involved in the up-regulation of 5-LO mRNA expression. To analyse the chromatin modifications at the 5-LO promoter associated with HDAC inhibition, the time course of 5-LO mRNA induction by trichostatin A was investigated and the concomitant changes in histone modifications at the 5-LO promoter in HL-60, U937 and Mono Mac6 cells were determined. Chromatin immunoprecipitation analysis revealed that trichostatin A increases acetylation of histones H3 and H4 at the 5-LO core promoter in HL-60 and U937 cells whereas no significant changes were observed in Mono Mac6 cells. The appearance of H3 and H4 acetylation preceded the 5-LO mRNA induction whereas in all three cell lines, induction of 5-LO mRNA expression correlated with histone H3 lysine 4 trimethylation (H3K4me3), a marker for transcriptional activity of gene promoters.
authors: Institute of Pharmaceutical Chemistry/ZAFES, Goethe University Frankfurt, Frankfurt, Germany.
authors: Laura
authors: L
authors: Pufahl
authors: Careen
authors: C
authors: Katryniok
authors: Nicole
authors: N
authors: Schnur
authors: Bernd L
authors: BL
authors: Sorg
authors: Julia
authors: J
authors: Metzner
authors: Manuel
authors: M
authors: Grez
authors: Dieter
authors: D
authors: Steinhilber
mesh_terms: D000107:Acetylation / Q000187:drug effects; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics* / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology; D047369:Chromatin Immunoprecipitation; D018922:HL-60 Cells; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000235:genetics / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D020298:U937 Cells; D015854:Up-Regulation; D000099186:Histone Deacetylase 3
chemical_list: D001094:Arachidonate 5-Lipoxygenase; D001549:Benzamides; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006657:Histones; D006877:Hydroxamic Acids; D010456:Peptides, Cyclic; D011725:Pyridines; D012333:RNA, Messenger; D014157:Transcription Factors; D000099186:Histone Deacetylase 3; C102351:apicidin; C118739:entinostat; C012589:trichostatin A; C110550:HDAC1 protein, human; C533423:HDAC2 protein, human