RT Journal Article
SR Electronic
T1 Interleukin-8 Expression Is Regulated by Histone Deacetylases through the Nuclear Factor-κB Pathway in Breast Cancer
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1359
OP 1366
DO 10.1124/mol.108.047332
VO 74
IS 5
A1 Carine Chavey
A1 Marcus Mühlbauer
A1 Carine Bossard
A1 Ariane Freund
A1 Sébastien Durand
A1 Christian Jorgensen
A1 Christian Jobin
A1 Gwendal Lazennec
YR 2008
UL http://molpharm.aspetjournals.org/content/74/5/1359.abstract
AB We have reported recently that the chemokine interleukin 8 (IL-8)/CXCL8 was overexpressed in invasive estrogen receptor (ERα)-negative breast cancer cells compared with ERα-positive breast cancer cells. We now demonstrate that histone deacetylases (HDACs) play an essential role in the regulation of IL-8 gene expression in ERα-positive MCF-7 breast cancer cells. Treatment of MCF-7 cells with the HDAC inhibitor trichostatin A (TSA) led to a strong up-regulation of IL-8 protein and RNA levels in MCF-7 cells. The up-regulation of IL-8 in MCF-7 cells was time- and concentration-dependent. Moreover, run-on and transfection experiments demonstrated that IL-8 induction by HDAC inhibitors was transcriptional and involved mainly the nuclear factor-κB (NF-κB) site of the IL-8 promoter. These observations are corroborated by an up-regulation of NF-κB activity in MCF-7 cells in the presence of TSA. In addition, blocking NF-κB pathway by adenoviral delivery of a dominant-negative IκBorIκB kinase complex 2 (IKK2) mutant abolished IL-8 gene induction by histone deacetylase inhibitors. HDAC inhibitors triggered IKK phosphorylation and up-regulated p65 nuclear translocation, although they decreased the protein levels of IκBα, which accounts for NF-κB activation. TSA increased binding of acetylated histone 3 to the IL-8 gene promoter. In summary, our results demonstrate that NF-κB pathway repression by HDAC is responsible for the low expression of IL-8 in ERα-positive breast cancer cells. The American Society for Pharmacology and Experimental Therapeutics