Histone deacetylase inhibitors block nuclear factor-κB-dependent transcription by interfering with RNA polymerase II recruitment

Ryohei Furumai, Akihiro Ito, Kenji Ogawa, Satoko Maeda, Akiko Saito, Norikazu Nishino, Sueharu Horinouchi, Minoru Yoshida
2011 Cancer Science  
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-a (TNF-a) production in rats and TNF-a-induced expression of inflammatory genes in HeLa cells. We assessed the molecular mechanism underlying TSA-induced anti-inflammatory activity by genetically dissecting activation of
more » ... ting activation of the nuclear factor-jB (NF-jB) pathway following stimulation with TNF-a. Trichostatin A did not inhibit degradation of IjBa, nuclear translocation and DNA binding of NF-jB; also, the drug did not affect transient expression from exogenous jB-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-jBinduced transcription. Indeed, chromatin immunoprecipitation (ChIP) analysis showed that events related to transcriptional activation of the IL-8 gene region in response to TNF-a, 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
doi:10.1111/j.1349-7006.2011.01904.x pmid:21299717 fatcat:swgd5sifovakhecub2qcztahwy