Sumoylation of HDAC2 promotes NF-?B-dependent gene expression.

ABSTRACT: The transcription factor nuclear factor-?B (NF-?B) is crucial for the maintenance of homeostasis. It is incompletely understood how nuclear NF-?B and the crosstalk of NF-?B with other transcription factors are controlled. Here, we demonstrate that the epigenetic regulator histone deacetylase 2 (HDAC2) activates NF-?B 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-?B through HDAC2. The expression of wild-type HDAC2 can increase the nuclear presence of NF-?B. In addition, the ribosomal S6 kinase 1 (RSK1) and the tumor suppressor p53 contribute to the regulation of NF-?B 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-?B signaling involving p53 and RSK1. Since HDAC2-dependent NF-?B 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-?B and of the NF-?B/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.

SUBMITTER: Wagner T 

PROVIDER: S-EPMC4466673 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature