Interleukin-8 expression is regulated by histone deacetylases through the nuclear factor-kappaB pathway in breast cancer.
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.
Chavey
Carine
C
Institut National de la Santé et de la Recherche Mé dicale, U844, University of Montpellier I, 34091 Montpellier cedex 5, France.
Mühlbauer
Marcus
M
Bossard
Carine
C
Freund
Ariane
A
Durand
Sébastien
S
Jorgensen
Christian
C
Jobin
Christian
C
Lazennec
Gwendal
G
D000256:Adenoviridae / Q000235:genetics; D001483:Base Sequence; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D011995:Recombination, Genetic; D015398:Signal Transduction
D017931:DNA Primers; D016209:Interleukin-8; D016328:NF-kappa B; D012333:RNA, Messenger; D006655:Histone Deacetylases