title: Sumoylation of HDAC2 promotes NF-κB-dependent gene expression.
abstract: The transcription factor nuclear factor-κB (NF-κB) is crucial for the maintenance of homeostasis. It is incompletely understood how nuclear NF-κB and the crosstalk of NF-κB with other transcription factors are controlled. Here, we demonstrate that the epigenetic regulator histone deacetylase 2 (HDAC2) activates NF-κB in transformed and primary cells. This function depends on both, the catalytic activity and an intact HDAC2 sumoylation motif. Several mechanisms account for the induction of NF-κB through HDAC2. The expression of wild-type HDAC2 can increase the nuclear presence of NF-κB. In addition, the ribosomal S6 kinase 1 (RSK1) and the tumor suppressor p53 contribute to the regulation of NF-κB by HDAC2. Moreover, TP53 mRNA expression is positively regulated by wild-type HDAC2 but not by sumoylation-deficient HDAC2. Thus, sumoylation of HDAC2 integrates NF-κB signaling involving p53 and RSK1. Since HDAC2-dependent NF-κB activity protects colon cancer cells from genotoxic stress, our data also suggest that high HDAC2 levels, which are frequently found in tumors, are linked to chemoresistance. Accordingly, inhibitors of NF-κB and of the NF-κB/p53-regulated anti-apoptotic protein survivin significantly sensitize colon carcinoma cells expressing wild-type HDAC2 to apoptosis induced by the genotoxin doxorubicin. Hence, the HDAC2-dependent signaling node we describe here may offer an interesting therapeutic option.
authors.affiliation: Centre for Molecular Biomedicine, Institute of Biochemistry and Biophysics, Department of Biochemistry, Friedrich Schiller University of Jena, Jena, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Wagner
authors.affiliation: Department of Toxicology, University Medical Center, Mainz, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Kiweler
authors.affiliation: Centre for Molecular Biomedicine, Institute of Biochemistry and Biophysics, Department of Biochemistry, Friedrich Schiller University of Jena, Jena, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Wolff
authors.affiliation: Centre for Medical Biotechnology, Molecular Biology II, University of Duisburg-Essen, Essen, Germany.
authors.forename: Shirley K
authors.initials: SK
authors.lastname: Knauer
authors.affiliation: Centre for Molecular Biomedicine, Institute of Biochemistry and Biophysics, Department of Biochemistry, Friedrich Schiller University of Jena, Jena, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Brandl
authors.affiliation: Leibniz-Institute for Age Research, Fritz-Lipmann-Institute, Jena, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Hemmerich
authors.affiliation: Division of Gene Regulation, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Jan-Hermen
authors.initials: JH
authors.lastname: Dannenberg
authors.affiliation: Centre for Molecular Biomedicine, Institute of Biochemistry and Biophysics, Department of Biochemistry, Friedrich Schiller University of Jena, Jena, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Heinzel
authors.affiliation: Klinikum rechts der Isar, II. Medizinische Klinik, Technische Universität München, München, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Schneider
authors.affiliation: Department of Toxicology, University Medical Center, Mainz, Germany.
authors.forename: Oliver H
authors.initials: OH
authors.lastname: Krämer
mesh_terms: D000818:Animals; D017209:Apoptosis; D002384:Catalysis; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D057809:HEK293 Cells; D056464:Histone Deacetylase 2 / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D051379:Mice; D009153:Mutagens / Q000737:chemistry; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction; D058207:Sumoylation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D009153:Mutagens; D016328:NF-kappa B; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2
keywords: RSK1; SUMO; histone deacetylase 2; p53; p65