Our previous studies have demonstrated the involvement of HIF-1 and p53 in the regulation of stanniocalcin-1 (STC1) gene transcription in human
cancer cells. In this study, we reported that the treatment of human colon
adenoma HT29 cells with a
histone deacetylase (
HDAC) inhibitor (i.e.
trichostatin A,
TSA) induced both cellular apoptosis and STC1 expression. The activation of STC1 expression was also observed in other
TSA-treated human
cancer cells (i.e. SKOV3, CaCo-2, Jurkat and CNE-2 cells). STC1
mRNA was rapidly induced within 4 h in
TSA-treated HT29 cells, and was found to be transcriptionally regulated and was independent of new
protein synthesis as revealed by ActD and CHX treatment respectively. The induction was correlated with increased cellular levels of acetyl
histone H3 and H4 and acetyl NFkappaB.
Chromatin immunoprecipitation (ChIP) assay showed the increased binding of acetyl
histone H3 and H4 to STC1 promoter in the
TSA-treated cells. A cotreatment of HT29 cells with a NFkappaB inhibitor (
parthenolide) significantly inhibited the
TSA-induced cellular levels of acetyl NFkappaB p65 and abolished the stimulation of STC1 gene expression. ChIP assay also demonstrated that
TSA treatment increased while
TSA/
parthenolide cotreatment decreased NFkappaB p65 binding to STC1 gene promoter. In the STC1-luciferase promoter construct (1 kb) study, the data implied that the promoter can be activated by
TSA treatment. Interestingly, the promoter region contains 2 putative NFkappaB binding sites. Consistent with the STC1mRNA expression data,
TSA/
parthenolide cotreatment also significantly inhibited the
TSA-induced STC1 promoter-driven
luciferase activity. Importantly,
TSA-induced apoptotic process was found to be significantly reduced by the silencing of STC1 expression. This is the first study to show that
histone hyper-acetylation and the recruitment of activated NFkappaB stimulated STC1 gene expression. In addition, our results support the notion that STC1 is a pro-apoptotic factor.