Sumoylation of HDAC2 promotes NF-κB-dependent gene expression

Tobias Wagner, Nicole Kiweler, Katharina Wolff, Shirley K. Knauer, André Brandl, Peter Hemmerich, Jan Hermen Dannenberg, Thorsten Heinzel, Günter Schneider, Oliver H. Krämer*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

35 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)7123-7135
Number of pages13
JournalOncotarget
Volume6
Issue number9
DOIs
Publication statusPublished - 2015
Externally publishedYes

Keywords

  • Histone deacetylase 2
  • P53
  • P65
  • RSK1
  • SUMO

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