Sumoylation of HDAC2 promotes NF-κB-dependent gene expression
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Tobias Wagner1, Nicole Kiweler2, Katharina Wolff1, Shirley K. Knauer3, André Brandl1, Peter Hemmerich4, Jan-Hermen Dannenberg5, Thorsten Heinzel1, Günter Schneider6 and Oliver H. Krämer2
1 Centre for Molecular Biomedicine, Institute of Biochemistry and Biophysics, Department of Biochemistry, Friedrich Schiller University of Jena, Jena, Germany
2 Department of Toxicology, University Medical Center, Mainz, Germany
3 Centre for Medical Biotechnology, Molecular Biology II, University of Duisburg-Essen, Essen, Germany
4 Leibniz-Institute for Age Research, Fritz-Lipmann-Institute, Jena, Germany
5 Division of Gene Regulation, Netherlands Cancer Institute, Amsterdam, The Netherlands
6 Klinikum rechts der Isar, II. Medizinische Klinik, Technische Universität München, München, Germany
Oliver H. Krämer, email:
Keywords: Histone deacetylase 2, p53, p65, RSK1, SUMO
Received: January 02, 2015 Accepted: January 04, 2015 Published: January 21, 2015
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.
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