Interleukin-8 Expression Is Regulated by Histone Deacetylases through the Nuclear Factor-κB Pathway in Breast Cancer
- 30 July 2008
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Molecular Pharmacology
- Vol. 74 (5), 1359-1366
- https://doi.org/10.1124/mol.108.047332
Abstract
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.Keywords
This publication has 42 references indexed in Scilit:
- CXC chemokines located in the 4q21 region are up-regulated in breast cancerEndocrine-Related Cancer, 2007
- Chemokines: novel targets for breast cancer metastasisCancer and Metastasis Reviews, 2007
- Oestrogen receptor negative breast cancers exhibit high cytokine contentBreast Cancer Research, 2007
- ERα and ERβ expression and transcriptional activity are differentially regulated by HDAC inhibitorsOncogene, 2005
- Potentiation of Tumor Necrosis Factor-Induced NF-κB Activation by Deacetylase Inhibitors Is Associated with a Delayed Cytoplasmic Reappearance of IκBαMolecular and Cellular Biology, 2003
- A nucleosomal function for IκB kinase-α in NF-κB-dependent gene expressionNature, 2003
- IL-8 expression and its possible relationship with estrogen-receptor-negative status of breast cancer cellsOncogene, 2003
- Butyrate modulates intestinal epithelial cell-mediated neutrophil migrationClinical and Experimental Immunology, 2003
- The p65 (RelA) Subunit of NF-κB Interacts with the Histone Deacetylase (HDAC) Corepressors HDAC1 and HDAC2 To Negatively Regulate Gene ExpressionMolecular and Cellular Biology, 2001
- Duration of Nuclear NF-κB Action Regulated by Reversible AcetylationScience, 2001