Received for publication March 19, 2008.
Revised July 29, 2008.
Accepted for publication July 30, 2008.

Interleukin-8 expression is regulated by histone deacetylases through the NF-B pathway in breast cancer

Abstract

We have recently reported that the chemokine IL-8/CXCL8 was overexpressed in invasive estrogen receptor (ER)-negative breast cancer cells, compared to ER-positive breast cancer cells. We now demonstrate that histone deacetylases (HDAC) play an essential role in the regulation of IL-8 gene expression in ER-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 NF-B site of the IL-8 promoter. These observations are corroborated by an up-regulation of NF-B activity in MCF-7 cells in the presence of TSA. In addition, blocking NF-B pathway by adenoviral delivery of a dominant-negative IB or IKK2 mutant abolished IL-8 gene induction by histone deacetylase inhibitors. HDAC inhibitors triggered IKK phosphorylation, up-regulated p65 nuclear translocation, while decreasing the protein levels of IB, which accounts for NF-B activation. TSA increased binding of acetylated histone 3 (H3) to the IL-8 gene promoter. In summary, our results demonstrate that NF-B pathway repression by HDAC is responsible for the low expression of IL-8 in ER-positive breast cancer cells.

Key words: Interleukins, NFkappaB, Oncogenes