Mechanism for fetal hemoglobin induction by histone deacetylase inhibitors involves γ-globin activation by CREB1 and ATF-2
Open Access
- 15 November 2006
- journal article
- Published by American Society of Hematology in Blood
- Vol. 108 (10), 3590-3599
- https://doi.org/10.1182/blood-2006-01-023713
Abstract
The histone deacetylase inhibitors (HDA-CIs) butyrate and trichostatin A activate γ-globin expression via a p38 mitogen-activating protein kinase (MAPK)-dependent mechanism. We hypothesized that down-stream 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.Keywords
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