RESUMO
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.
Assuntos
Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Histona Desacetilase 2/metabolismo , NF-kappa B/metabolismo , Sumoilação , Animais , Apoptose , Catálise , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Neoplasias do Colo/metabolismo , Fibroblastos/metabolismo , Genes Reporter , Células HEK293 , Homeostase , Humanos , Camundongos , Mutagênicos/química , Transdução de Sinais , Proteína Supressora de Tumor p53/genéticaRESUMO
Histone deacetylase 2 (HDAC2) is relevant for homeostasis and plays a critical role in gastrointestinal cancers. Here, we report that post-translational modification of endogenous HDAC2 with small ubiquitin-related modifier 1 (SUMO1) is a new regulatory switch for the tumor suppressor p53. Sumoylation of HDAC2 at lysine 462 allows binding of HDAC2 to p53. Moreover, sumoylated HDAC2 is a previously not recognized biologically relevant site-specific deacetylase for p53. Deacetylation of p53 at lysine 320 by sumoylated HDAC2 blocks recruitment of p53 into promoter-associated complexes and p53-dependent expression of genes for cell cycle control and apoptosis. Thereby, catalytically active sumoylated HDAC2 restricts p53 functions and attenuates DNA damage-induced apoptosis. Genotoxic stress evokes desumoylation of HDAC2, enabling p53-dependent gene expression. Our data show a new molecular mechanism involving a dynamically controlled HDAC2-sumoylation/p53-acetylation switch that regulates cell fate decisions following genotoxic stress.
Assuntos
Apoptose , Dano ao DNA , Histona Desacetilase 2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Acetilação , Linhagem Celular Tumoral , Células HCT116 , Células HEK293 , Células HeLa , Histona Desacetilase 2/genética , Humanos , Processamento de Proteína Pós-Traducional , Sumoilação , Transcrição Gênica , Transfecção , Proteína Supressora de Tumor p53/genéticaRESUMO
HDACs (histone deacetylases) are enzymes that remove the acetyl moiety from N-epsilon-acetylated lysine residues in histones and non-histone proteins. In recent years, it has turned out that HDACs themselves are also subject to post-translational modification. Such structural alterations can determine the stability, localization, activity and protein-protein interactions of HDACs. This subsequently affects the modification of their substrates and the co-ordination of cellular signalling networks. Intriguingly, physiologically relevant non-histone proteins are increasingly found to be deacetylated by HDACs, and aberrant deacetylase activity contributes to several severe human diseases. Targeting the catalytic activity of these enzymes and their post-translational modifications are therefore attractive targets for therapeutical intervention strategies. To achieve this ambitious goal, details on the molecular mechanisms regulating post-translational modifications of HDACs are required. This review summarizes aspects of the current knowledge on the biological role and enzymology of the phosphorylation, acetylation, ubiquitylation and sumoylation of HDACs.