HDAC Activity Is Required for p65/RelA-Dependent Repression of PPARδ-Mediated Transactivation in Human Keratinocytes

Abstract

Peroxisome proliferator-activated receptors (PPARs) play a key role in differentiation, inflammation, migration, and survival of epidermal keratinocytes. The NF-kappaB has long been known to play pivotal roles in immune and inflammatory responses, and furthermore NF-kappaB has been implicated in the regulation of epidermal homeostasis. Recent studies have established that p65/RelA is a potent repressor of PPARdelta-mediated transactivation in human keratinocytes. In this article we further investigate the molecular mechanisms dictating the NF-kappaB-dependent repression of PPARdelta in human keratinocytes. We demonstrate that repression is unique to p65/RelA, as no other member of the NF-kappaB family had an impact on PPARdelta-mediated transactivation. Interestingly, our results show that p65/RelA only represses PPARdelta-dependent transactivation when PPARdelta is bound to DNA via its DNA-binding domain. We show that repression is sensitive to inhibition of histone deacetylases (HDACs) by tricostatin A (TSA), suggesting that HDAC activity is indispensable for p65/RelA-mediated repression. Accordingly, we demonstrate that a ternary complex consisting of PPARdelta, p65/RelA, and HDAC1 is formed in vivo. Finally, we demonstrate that TSA relieves tumor necrosis factor-alpha (TNFalpha)-induced repression of PPARdelta-mediated transactivation of the PPARdelta target gene adipose differentiation-related protein (ADRP) indicating that cross-talk between PPARdelta and NF-kappaB is of biological significance in human keratinocytes.

The Inflammatory Cytokines TWEAK and TNFα Reduce Renal Klotho Expression through NFκB

“…HDAC activity is required for p65/RelA-dependent repression of PPAR␦ in human keratinocytes, of antiapoptotic genes in fibroblasts, and of PDGF in smooth muscle cells. 37,53,54 We observed that TWEAK and TNF␣ increased nuclear RelA association with nuclear HDAC1 at the same time that Klotho expression was decreased in tubular cells. This result suggested that TWEAK-and TNF␣-induced Klotho downregulation could be mediated by HDAC activity.…”

Warburg effect revisited: an epigenetic link between glycolysis and gastric carcinogenesis

“…However, murine FBP1 has no CGI, indicating that promoter methylation is unlikely the mechanism responsible for NF-kappaB-dependent FBP1 downregulation in Rastransformed NIH3T3 cells. NF-kappaB could inhibit the transcription of target genes through the interaction with some transcription corepressors such as histone Aarenstrup et al, 2008;Bhat et al, 2008). HDACs could in turn interact with DNA methyltransferases (DNMTs) such as DNMT1 and DNMT3B (Fuks et al, 2000;Robertson et al, 2000;Rountree et al, 2000).…”

NF-κB in Renal Inflammation

“…1 NF-B may also function as a repressor of gene expression through various mechanisms: Inactive complexes, competitions of the RelA subunit with co-activators of transcription, posttranslational modifications of RelA that regulate its function as either an activator or a repressor of gene expression, and posttranslational modification of histones surrounding the NF-B target genes. [32][33][34][35][36] Homo-or heterodimers of p50 and p52 repress B site-dependent transcription possibly as a result of competition for DNA binding with other transcriptionally active dimers, such as p50/RelA. 37 Suppressors of cytokine signaling 1 forms part of a nuclear protein complex that promotes the ubiquitylation and proteasomal degradation of RelA-containing dimers, thus quenching NF-B responses.…”