Sumoylation of HDAC2 promotes NF-κB-dependent gene expression

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.

Histone/protein deacetylase inhibitor therapy for enhancement of Foxp3+ T-regulatory cell function posttransplantation

“…27 Individual pharmacologic targeting of Hdac1 vs. Hdac2 is considered very difficult given the nearly identical nature of the their active sites and surrounding surfaces, but there are reports of small molecules that show different dissociation rates for Hdac1 vs. Hdac2; such kinetically-selective Hdac2 inhibitors enhance Treg function in vitro but have not been tested in vivo . 28, 29 An alternate approach is to target the functions of the HDAC-associated complex, though the core components and their partnering molecules may vary by cell type and function. 30 An example of this approach, in the case of the CoREST complex, was the development of dual inhibitors of the HDAC and demethylase activities of the complex, 31 and these inhibitors are under investigation for their effects on Tregs.…”

Histone deacetylase 2 is involved in DNA damage‐mediated cell death of human osteosarcoma cells through stimulation of the ATM/p53 pathway

“…For example, Wagner et al . described that higher expression level of HDAC2 is closely linked to cisplatin resistance of colon cancer cells. Fritsche et al .…”

“…In contrast to our present results, mounting evidence indicates that HDAC2 is aberrantly overexpressed in a variety of cancer tissues and implicated in the promotion of malignant phenotypes of certain cancer cells such as anti-cancer drug resistance. For example, Wagner et al [17] described that higher expression level of HDAC2 is closely linked to cisplatin resistance of colon cancer cells. Fritsche et al [18] revealed that HDAC2 contributes to the resistance to etoposide of pancreatic cancer cells.…”

An activity-guided map of electrophile-cysteine interactions in primary human immune cells

“…Despite this mechanistic uncertainty, our studies have uncovered a remarkably selective, electrophile-mediated process for degradation of a key transcriptional regulatory complex in primary human T cells. Considering that HDAC inhibitors have been previously shown to block T cell activation (Takahashi et al, 1996), and HDACs can also support NF-kB function (Jung et al, 2009;Kumar et al, 2017;Wagner et al, 2015), it is possible that the BPK-25-mediated loss of the NuRD complex is relevant to the T cell-suppressive activity of this compound.…”