title: C/EBPα and C/EBPα oncoproteins regulate nfkb1 and displace histone deacetylases from NF-κB p50 homodimers to induce NF-κB target genes.
abstract: Mutated CEBPA defines a subgroup of acute myeloid leukemia (AML). We have previously shown that C/EBPα or its AML mutants synergize with NF-κB p50 to activate antiapoptotic genes, including BCL2 and FLIP. Furthermore, p50 binds and activates the CEBPA gene in myeloid cells. We now report that C/EBPα or C/EBPα leucine zipper AML mutants bind in vivo to the nfkb1 (p50) promoter and induce its expression even in the presence of cycloheximide. Induction of p50 by C/EBPα depends on 2 conserved κB sites in the nfkb1 promoter. C/EBPα did not induce p65 expression. Thus, C/EBPα and p50 reciprocally regulate each other's expression, establishing a positive feedback relationship. Although p50 homodimers inhibit transcription, C/EBPα and p50 synergistically activate antiapoptotic genes. ChIP analysis showed that C/EBPα diminishes the occupation of histone deacetylase 1 (HDAC1) or HDAC3 on the endogenous FLIP promoter but not in mice lacking p50. Coimmunoprecipitation confirmed that C/EBPα, its AML variants, or C/EBPβ disrupt interaction between p50 and HDACs dependent on the C/EBP basic region. These findings suggest that C/EBPs displace HDACs from p50 homodimers bound to antiapoptotic genes, contributing to NF-κB dysregulation in leukemia, and that the C/EBPα:p50 complex is a potential therapeutic target.
authors.affiliation: Division of Pediatric Oncology, Johns Hopkins University, Baltimore, MD, USA. ipazpri1@jhmi.edu
authors.forename: Ido
authors.initials: I
authors.lastname: Paz-Priel
authors.forename: Simone
authors.initials: S
authors.lastname: Houng
authors.forename: Julia
authors.initials: J
authors.lastname: Dooher
authors.forename: Alan D
authors.initials: AD
authors.lastname: Friedman
mesh_terms: D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D019281:Dimerization; D015973:Gene Expression Regulation, Leukemic / Q000502:physiology*; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D052002:NF-kappa B p50 Subunit / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C530718:CEBPA protein, mouse; D052002:NF-kappa B p50 Subunit; C073701:Nfkb1 protein, mouse; D006655:Histone Deacetylases