Induction of fetal hemoglobin expression by the histone deacetylase inhibitor apicidin.

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.

[1]  R. Reeves,et al.  Sodium butyrate inhibits histone deacetylation in cultured cells , 1978, Cell.

[2]  Alan P. Wolffe,et al.  Disruption of Higher-Order Folding by Core Histone Acetylation Dramatically Enhances Transcription of Nucleosomal Arrays by RNA Polymerase III , 1998, Molecular and Cellular Biology.

[3]  Philip R. Cohen,et al.  SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin‐1 , 1995, FEBS letters.

[4]  N. Olivieri.  The β-Thalassemias , 1999 .

[5]  D M Schmatz,et al.  Apicidin: a novel antiprotozoal agent that inhibits parasite histone deacetylase. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[6]  M. Nishiyama,et al.  Histone deacetylase as a new target for cancer chemotherapy , 2001, Cancer Chemotherapy and Pharmacology.

[7]  I. Z. Ades.  Transport of newly synthesized proteins into mitochondria — a review , 1982, Molecular and Cellular Biochemistry.

[8]  G. Henze,et al.  Oral isobutyramide reduces transfusion requirements in some patients with homozygous β-thalassemia , 2000 .

[9]  D. Faller,et al.  A short-term trial of butyrate to stimulate fetal-globin-gene expression in the beta-globin disorders. , 1993, The New England journal of medicine.

[10]  O. Witt,et al.  Tumor cell differentiation by butyrate and environmental stress. , 2001, Cancer letters.

[11]  Y Nagata,et al.  Activation of p38 MAP kinase and JNK but not ERK is required for erythropoietin-induced erythroid differentiation. , 1998, Blood.

[12]  G. Stamatoyannopoulos,et al.  Fetal hemoglobin induction with butyric acid: efficacy and toxicity. , 1993, Blood.

[13]  H. W. Lee,et al.  Apicidin, a histone deacetylase inhibitor, inhibits proliferation of tumor cells via induction of p21WAF1/Cip1 and gelsolin. , 2000, Cancer research.

[14]  E. Krebs,et al.  The MAPK signaling cascade , 1995, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[15]  A. Schechter,et al.  Quantitative PCR analysis of HbF inducers in primary human adult erythroid cells. , 2000, Blood.

[16]  B. Alberts,et al.  Different accessibilities in chromatin to histone acetylase. , 1979, The Journal of biological chemistry.

[17]  D. Doenecke,et al.  Acetylation of histones in nucleosomes , 1982, Molecular and Cellular Biochemistry.

[18]  E. Bresnick,et al.  Developmentally dynamic histone acetylation pattern of a tissue-specific chromatin domain. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[19]  Jerry L. Adams,et al.  A protein kinase involved in the regulation of inflammatory cytokine biosynthesis , 1994, Nature.

[20]  K. Nightingale,et al.  Histone acetylation facilitates RNA polymerase II transcription of the Drosophila hsp26 gene in chromatin , 1998, The EMBO journal.

[21]  M. Yoshida,et al.  Effects of trichostatins on differentiation of murine erythroleukemia cells. , 1987, Cancer research.

[22]  S. Brusilow,et al.  Induction of fetal hemoglobin production in subjects with sickle cell anemia by oral sodium phenylbutyrate. , 1994, Blood.

[23]  A. Wolffe,et al.  Structure and function of the core histone N-termini: more than meets the eye. , 1998, Biochemistry.

[24]  Y. Saunthararajah,et al.  Advances in experimental treatment of beta-thalassaemia. , 2001, Expert opinion on investigational drugs.

[25]  J. Davie,et al.  Histone Acetylation Is Required to Maintain the Unfolded Nucleosome Structure Associated with Transcribing DNA* , 1998, The Journal of Biological Chemistry.

[26]  D. Loukopoulos,et al.  Pharmacological induction of fetal hemoglobin in sickle cell disease and beta-thalassemia. , 2001, Seminars in hematology.

[27]  Y. Saunthararajah,et al.  Advances in experimental treatment of β-thalassaemia , 2001 .

[28]  G. Henze,et al.  Oral isobutyramide reduces transfusion requirements in some patients with homozygousb-thalassemia , 2000 .

[29]  D E Griswold,et al.  Pharmacological profile of SB 203580, a selective inhibitor of cytokine suppressive binding protein/p38 kinase, in animal models of arthritis, bone resorption, endotoxin shock and immune function. , 1996, The Journal of pharmacology and experimental therapeutics.

[30]  F. Hobbs,et al.  Identification of a Novel Inhibitor of Mitogen-activated Protein Kinase Kinase* , 1998, The Journal of Biological Chemistry.

[31]  M. Su,et al.  Induction of gamma-globin by histone deacetylase inhibitors. , 1997, Blood.

[32]  N. Olivieri.  The beta-thalassemias. , 1999, The New England journal of medicine.

[33]  M. Su,et al.  Induction of γ-Globin by Histone Deacetylase Inhibitors , 1997 .

[34]  K. Todokoro,et al.  Requirement of activation of JNK and p38 for environmental stress-induced erythroid differentiation and apoptosis and of inhibition of ERK for apoptosis. , 1999, Blood.

[35]  O. Witt,et al.  Transcriptional regulation of the human replacement histone gene H3.3B , 1997, FEBS letters.

[36]  N. Olivieri,et al.  Extended therapy with intravenous arginine butyrate in patients with beta-hemoglobinopathies. , 1995, The New England journal of medicine.

[37]  N. Ahn,et al.  Signal transduction through MAP kinase cascades. , 1998, Advances in cancer research.

[38]  O. Witt,et al.  Butyrate-induced erythroid differentiation of human K562 leukemia cells involves inhibition of ERK and activation of p38 MAP kinase pathways. , 2000, Blood.