Open AccessHistone deacetylase inhibitors block nuclear factor‐κB‐dependent transcription by interfering with RNA polymerase II recruitment
Author(s) -
Furumai Ryohei,
Ito Akihiro,
Ogawa Kenji,
Maeda Satoko,
Saito Akiko,
Nishino Norikazu,
Horinouchi Sueharu,
Yoshida Minoru
Publication year - 2011
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2011.01904.x
Subject(s) - trichostatin a , histone deacetylase , microbiology and biotechnology , chromatin immunoprecipitation , rna polymerase ii , biology , small interfering rna , transcription factor , histone deacetylase inhibitor , histone deacetylase 5 , gene expression , chemistry , histone , promoter , rna , biochemistry , gene
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. ( Cancer Sci 2011; 102: 1081–1087)