Histone deacetylase inhibitors block nuclear factor-κB-dependent transcription by interfering with RNA polymerase II recruitment
| Autor: | Norikazu Nishino, Minoru Yoshida, Akiko Saito, Kenji Ogawa, Akihiro Ito, Sueharu Horinouchi, Ryohei Furumai, Satoko Maeda |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Chromatin Immunoprecipitation
Cancer Research Transcription Genetic medicine.drug_class Blotting Western Fluorescent Antibody Technique Gene Expression RNA polymerase II Hydroxamic Acids Transcription (biology) medicine Animals Humans Inflammation Histone deacetylase 5 biology Reverse Transcriptase Polymerase Chain Reaction Histone deacetylase inhibitor NF-kappa B General Medicine Molecular biology Rats Histone Deacetylase Inhibitors IκBα Trichostatin A Oncology biology.protein RNA Polymerase II Histone deacetylase Chromatin immunoprecipitation HeLa Cells medicine.drug |
| Zdroj: | Cancer Science. 102:1081-1087 |
| ISSN: | 1347-9032 |
| DOI: | 10.1111/j.1349-7006.2011.01904.x |
| Popis: | Histone deacetylase inhibitors (HDACi) have been shown to exhibit anti-inflammatory activity, but their mechanism of action is poorly understood. Trichostatin A (TSA) and the cyclic tetrapeptide class inhibitor Ky-2 inhibit both lipopolysaccharide-induced tumor necrosis factor-α (TNF-α) production in rats and TNF-α-induced expression of inflammatory genes in HeLa cells. We assessed the molecular mechanism underlying TSA-induced anti-inflammatory activity by genetically dissecting activation of the nuclear factor-κB (NF-κB) pathway following stimulation with TNF-α. Trichostatin A did not inhibit degradation of IκBα, nuclear translocation and DNA binding of NF-κB; also, the drug did not affect transient expression from exogenous κB-reporter plasmids. However, endogenous expression of inflammatory cytokines such as interleukin-8 (IL-8) was greatly reduced, even in the absence of de novo protein synthesis, suggesting that HDACi directly inhibits NF-κB-induced transcription. Indeed, chromatin immunoprecipitation (ChIP) analysis showed that events related to transcriptional activation of the IL-8 gene region in response to TNF-α, including recruitment of RNA polymerase II (Pol II), were compromised in the presence of TSA. These data indicate that HDAC activity is required for the efficient initiation and/or elongation of inflammatory gene transcription mediated by NF-κB. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text