Mechanism for fetal hemoglobin induction by histone deacetylase inhibitors involves γ-globin activation by CREB1 and ATF-2

Jose Sangerman, Seung Lee Moo, Xiao Yao, Eugene Oteng, Cheng Hui Hsiao, Wei Li, Sima Zein, Solomon F. Ofori-Acquah, Betty S. Pace

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58 Scopus citations

Abstract

The histone deacetylase inhibitors (HDACIs) butyrate and trichostatin A activate γ-globin expression via a p38 mitogen-activating protein kinase (MAPK)-dependent mechanism. We hypothesized that downstream effectors of p38 MAPK, namely activating transcription factor-2 (ATF-2) and cyclic AMP response element (CRE) binding protein (CREB), are intimately involved in fetal hemoglobin induction by these agents. In this study, we observed increased ATF-2 and CREB1 phosphorylation mediated by the HDACIs in K562 cells, in conjunction with histone H4 hyperacetylation. Moreover, enhanced DNA-protein interactions occurred in the CRE in the Gγ-globin promoter (G-CRE) in vitro after drug treatments; subsequent chromatin immunoprecipitation assay confirmed ATF-2 and CREB1 binding to the G-CRE in vivo. Enforced expression of ATF-2 and CREB produced Gγ-promoter trans-activation which was abolished by a 2-base pair mutation in the putative G-CRE. The data presented herein demonstrate that γ-gene induction by butyrate and trichostatin A involves ATF-2 and CREB1 activation via p38 MAPK signaling.

Original languageEnglish (US)
Pages (from-to)3590-3599
Number of pages10
JournalBlood
Volume108
Issue number10
DOIs
StatePublished - Nov 15 2006

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Sangerman, J., Moo, S. L., Yao, X., Oteng, E., Hsiao, C. H., Li, W., Zein, S., Ofori-Acquah, S. F., & Pace, B. S. (2006). Mechanism for fetal hemoglobin induction by histone deacetylase inhibitors involves γ-globin activation by CREB1 and ATF-2. Blood, 108(10), 3590-3599. https://doi.org/10.1182/blood-2006-01-023713