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Interleukin-8 expression is regulated by histone deacetylases through the nuclear factor-kappaB pathway in breast cancer.

Abstract : We have reported recently that the chemokine interleukin 8 (IL-8)/CXCL8 was overexpressed in invasive estrogen receptor (ERalpha)-negative breast cancer cells compared with ERalpha-positive breast cancer cells. We now demonstrate that histone deacetylases (HDACs) play an essential role in the regulation of IL-8 gene expression in ERalpha-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-kappaB (NF-kappaB) site of the IL-8 promoter. These observations are corroborated by an up-regulation of NF-kappaB activity in MCF-7 cells in the presence of TSA. In addition, blocking NF-kappaB pathway by adenoviral delivery of a dominant-negative IkappaBorIkappaB 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 IkappaBalpha, which accounts for NF-kappaB activation. TSA increased binding of acetylated histone 3 to the IL-8 gene promoter. In summary, our results demonstrate that NF-kappaB pathway repression by HDAC is responsible for the low expression of IL-8 in ERalpha-positive breast cancer cells.
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Contributor : Gwendal Lazennec <>
Submitted on : Monday, August 4, 2008 - 10:06:48 AM
Last modification on : Tuesday, December 1, 2020 - 5:00:06 PM
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Carine Chavey, Marcus Muhlbauer, Carine Bossard, Ariane Freund, Sebastien Durand, et al.. Interleukin-8 expression is regulated by histone deacetylases through the nuclear factor-kappaB pathway in breast cancer.. Molecular Pharmacology, American Society for Pharmacology and Experimental Therapeutics, 2008, 74 (5), pp.1359-66. ⟨10.1124/mol.108.047332⟩. ⟨inserm-00308891⟩



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