title: Induction of fetal hemoglobin expression by the histone deacetylase inhibitor apicidin.
abstract: Pharmacologic stimulation of fetal hemoglobin (HbF) expression may be a promising approach for the treatment of beta-thalassemia. In this study, we have investigated the HbF-inducing activity and molecular mechanisms of specific histone deacetylase (HDAC) inhibitors in human K562 erythroleukemia cells. Apicidin was the most potent agent compared with other HDAC inhibitors (trichostatin A, MS-275, HC-toxin, suberoylanilide hydroxamic acid [SAHA]) and previously tested compounds (butyrate, phenylbutyrate, isobutyramide, hydroxyurea, 5-aza-cytidine), leading to a 10-fold stimulation of HbF expression at nanomolar to micromolar concentrations. Hyperacetylation of histones correlated with the ability of HDAC inhibitors to stimulate HbF synthesis. Furthermore, analysis of different mitogen-activated protein (MAP) kinase signaling pathways revealed that p38 signaling was activated following apicidin treatment of cells and that inhibition of this pathway abolished the HbF-inducing effect of apicidin. Additionally, activation of the Agamma-globin promoter by apicidin could be inhibited by p38 inhibitor SB203580. In summary, the novel HDAC inhibitor apicidin was found to be a potent inducer of HbF synthesis in K562 cells. The present data outline the role of histone hyperacetylation and p38 MAP kinase signaling as molecular targets for pharmacologic stimulation of HbF production in erythroid cells.
authors.affiliation: Laboratory for Hematological and Cancer Research, Children's Hospital, University of Goettingen, Goettingen, Germany. owitt@gwdg.de
authors.forename: Olaf
authors.initials: O
authors.lastname: Witt
authors.forename: Sven
authors.initials: S
authors.lastname: Monkemeyer
authors.forename: Gabi
authors.initials: G
authors.lastname: Rönndahl
authors.forename: Bernhard
authors.initials: B
authors.lastname: Erdlenbruch
authors.forename: Dirk
authors.initials: D
authors.lastname: Reinhardt
authors.forename: Katrin
authors.initials: K
authors.lastname: Kanbach
authors.forename: Arnulf
authors.initials: A
authors.lastname: Pekrun
mesh_terms: D000577:Amides / Q000494:pharmacology; D001374:Azacitidine / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D002087:Butyrates / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005319:Fetal Hemoglobin / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D005914:Globins / Q000096:biosynthesis* / Q000235:genetics; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000502:physiology; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D006918:Hydroxyurea / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D020014:K562 Cells / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010654:Phenylbutyrates / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D000077337:Vorinostat; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D000577:Amides; D001549:Benzamides; D002087:Butyrates; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007093:Imidazoles; D009363:Neoplasm Proteins; D010456:Peptides, Cyclic; D010654:Phenylbutyrates; D011725:Pyridines; C102351:apicidin; C118739:entinostat; C012589:trichostatin A; D000077337:Vorinostat; C030197:isobutyramide; C037654:HC toxin; D005914:Globins; D005319:Fetal Hemoglobin; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D006655:Histone Deacetylases; D001374:Azacitidine; C093642:SB 203580; D006918:Hydroxyurea