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Sumoylation of HDAC2 promotes NF-κB-dependent gene expression.

Wagner T, Kiweler N, Wolff K, Knauer SK, Brandl A, Hemmerich P, Dannenberg JH, Heinzel T, Schneider G, Krämer OH - Oncotarget (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Centre for Molecular Biomedicine, Institute of Biochemistry and Biophysics, Department of Biochemistry, Friedrich Schiller University of Jena, Jena, Germany.

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.

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HDAC2 sumoylation integrates NF-κB signalingOur work reveals that the epigenetic regulator histone deacetylase 2 (HDAC2) can activate NF-κB-dependent gene expression in human cancer cells and in murine embryonic fibroblasts. We show that the posttranslational modification of HDAC2 with the small ubiquitin-related modifier (SUMO) integrates NF-κB p65 and the tumor suppressor p53. In the absence of HDAC2 sumoylation the activation of NF-κB by HDAC2 is strongly diminished. Our data further suggest that enhanced recruitment of p53 to NF-κB p65 bound to DNA and an increased nuclear accumulation of p65 are causal for an augmented NF-κB-dependent anti-apoptotic gene expression in cells expressing wild-type HDAC2. Additionally, we demonstrate that HDAC2, but not its sumoylation-deficient variant, increases the resistance of colon cancer cells toward genotoxic stress. These findings suggest that the HDAC2-NF-κB signaling node we report in our manuscript contributes to tumorigenesis and chemoresistance.
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Figure 5: HDAC2 sumoylation integrates NF-κB signalingOur work reveals that the epigenetic regulator histone deacetylase 2 (HDAC2) can activate NF-κB-dependent gene expression in human cancer cells and in murine embryonic fibroblasts. We show that the posttranslational modification of HDAC2 with the small ubiquitin-related modifier (SUMO) integrates NF-κB p65 and the tumor suppressor p53. In the absence of HDAC2 sumoylation the activation of NF-κB by HDAC2 is strongly diminished. Our data further suggest that enhanced recruitment of p53 to NF-κB p65 bound to DNA and an increased nuclear accumulation of p65 are causal for an augmented NF-κB-dependent anti-apoptotic gene expression in cells expressing wild-type HDAC2. Additionally, we demonstrate that HDAC2, but not its sumoylation-deficient variant, increases the resistance of colon cancer cells toward genotoxic stress. These findings suggest that the HDAC2-NF-κB signaling node we report in our manuscript contributes to tumorigenesis and chemoresistance.

Mentions: RSK1 has been described to be an important factor in coordinating the p53 crosstalk in situations when NF-κB is not activated by classical stimuli [12]. Accordingly, knockdown of either p53 or RSK1 in our setting abrogates the effect of HDAC2 towards NF-κB (Figures 3C and 4A). Additionally the presence of HDAC2 results in enhanced recruitment of p53 to NF-κB transcriptional complexes (Figure 3B). This cross-signaling between p53 and NF-κB proteins gives further insight in molecular mechanisms regulating tumorigenesis and might be a point of action for pharmacological intervention [9, 28, 29, 46]. In sum, our data show that HDAC2 sumoylation is important for NF-κB-dependent gene expression and for the resistance of cell against stress (Figure 5). Hence, monitoring the expression of HDAC2 and its sumoylation status could be of prognostic value and HDAC2 appear as a promising target for therapeutic intervention strategies.


Sumoylation of HDAC2 promotes NF-κB-dependent gene expression.

Wagner T, Kiweler N, Wolff K, Knauer SK, Brandl A, Hemmerich P, Dannenberg JH, Heinzel T, Schneider G, Krämer OH - Oncotarget (2015)

HDAC2 sumoylation integrates NF-κB signalingOur work reveals that the epigenetic regulator histone deacetylase 2 (HDAC2) can activate NF-κB-dependent gene expression in human cancer cells and in murine embryonic fibroblasts. We show that the posttranslational modification of HDAC2 with the small ubiquitin-related modifier (SUMO) integrates NF-κB p65 and the tumor suppressor p53. In the absence of HDAC2 sumoylation the activation of NF-κB by HDAC2 is strongly diminished. Our data further suggest that enhanced recruitment of p53 to NF-κB p65 bound to DNA and an increased nuclear accumulation of p65 are causal for an augmented NF-κB-dependent anti-apoptotic gene expression in cells expressing wild-type HDAC2. Additionally, we demonstrate that HDAC2, but not its sumoylation-deficient variant, increases the resistance of colon cancer cells toward genotoxic stress. These findings suggest that the HDAC2-NF-κB signaling node we report in our manuscript contributes to tumorigenesis and chemoresistance.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4466673&req=5

Figure 5: HDAC2 sumoylation integrates NF-κB signalingOur work reveals that the epigenetic regulator histone deacetylase 2 (HDAC2) can activate NF-κB-dependent gene expression in human cancer cells and in murine embryonic fibroblasts. We show that the posttranslational modification of HDAC2 with the small ubiquitin-related modifier (SUMO) integrates NF-κB p65 and the tumor suppressor p53. In the absence of HDAC2 sumoylation the activation of NF-κB by HDAC2 is strongly diminished. Our data further suggest that enhanced recruitment of p53 to NF-κB p65 bound to DNA and an increased nuclear accumulation of p65 are causal for an augmented NF-κB-dependent anti-apoptotic gene expression in cells expressing wild-type HDAC2. Additionally, we demonstrate that HDAC2, but not its sumoylation-deficient variant, increases the resistance of colon cancer cells toward genotoxic stress. These findings suggest that the HDAC2-NF-κB signaling node we report in our manuscript contributes to tumorigenesis and chemoresistance.
Mentions: RSK1 has been described to be an important factor in coordinating the p53 crosstalk in situations when NF-κB is not activated by classical stimuli [12]. Accordingly, knockdown of either p53 or RSK1 in our setting abrogates the effect of HDAC2 towards NF-κB (Figures 3C and 4A). Additionally the presence of HDAC2 results in enhanced recruitment of p53 to NF-κB transcriptional complexes (Figure 3B). This cross-signaling between p53 and NF-κB proteins gives further insight in molecular mechanisms regulating tumorigenesis and might be a point of action for pharmacological intervention [9, 28, 29, 46]. In sum, our data show that HDAC2 sumoylation is important for NF-κB-dependent gene expression and for the resistance of cell against stress (Figure 5). Hence, monitoring the expression of HDAC2 and its sumoylation status could be of prognostic value and HDAC2 appear as a promising target for therapeutic intervention strategies.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Centre for Molecular Biomedicine, Institute of Biochemistry and Biophysics, Department of Biochemistry, Friedrich Schiller University of Jena, Jena, Germany.

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.

Show MeSH
Related in: MedlinePlus