Abstract
While cyclooxygenase (COX)-2 is a highly inducible gene, COX-1 is widely known as a noninducible gene and is constitutively expressed in a variety of cell lines and human tissues. Recently, several reports have indicated that COX-1 is also regulated at the transcriptional level by various stimuli. We present evidence that histone deacetylase (HDAC) inhibitors induce COX-1 transcription and translation in normal human astrocyte (NHA) cells and glioma cell lines. HDAC inhibitors increased acetylated histone H4 protein expression in NHA cells. The levels of COX-1 mRNA and protein were maximal at 24 and 48 h, respectively, after treatment with the specific HDAC inhibitor, trichostatin A (TSA). In addition, TSA-treated NHA cells produced prostaglandin E(2) as determined by enzyme-linked immunosorbent assay after incubation with 10 microm exogenous arachidonic acid, indicating that the induced COX-1 is functionally active. In addition to NHA cells, this up-regulation of COX-1 after treatment with HDAC inhibitors was observed in 5 different glioma cell lines. The nucleotide sequence of the inducible COX-1 cDNA was confirmed identical to human COX-1 that was previously reported. HDAC inhibitors stimulated COX-1 promoter activity as measured by luciferase reporter assays, suggesting that the induction of COX-1 is regulated at the transcriptional level. Furthermore, mutation analysis of the COX-1 promoter suggests that TSA-responsive element exists in the proximal Sp1-binding site at +25 to +31. In conclusion, COX-1 is an inducible gene in glial-derived cells including immortalized cells, and appears to be transcriptionally regulated by a unique mechanism associated with histone acetylation.
Highlights
Cyclooxygenase (COX)1 is the key enzyme in the metabolic pathway leading to prostaglandins (PGs) and thromboxane A2 formation from arachidonic acid
In this report we have investigated the effects of histone deacetylase (HDAC) inhibitors on the expression of lipid metabolizing enzymes, COX-1, COX-2, and 15-LO-1, in human brain cell lines
Induction of COX-1 in normal human astrocyte (NHA) Cells after Treatment with HADC Inhibitors—To examine the effects of several HDAC inhibitors on the expression of lipid metabolizing enzymes in NHA cells, cells were treated with NaBT, HC toxin, and trichostatin A (TSA) for various times and doses
Summary
16823–16830, 2002 Printed in U.S.A. Transcriptional Regulation of Cyclooxygenase-1 by Histone Deacetylase Inhibitors in Normal Human Astrocyte Cells*. We present evidence that histone deacetylase (HDAC) inhibitors induce COX-1 transcription and translation in normal human astrocyte (NHA) cells and glioma cell lines. HDAC inhibitors increased acetylated histone H4 protein expression in NHA cells. HDAC inhibitors stimulated COX-1 promoter activity as measured by luciferase reporter assays, suggesting that the induction of COX-1 is regulated at the transcriptional level. In this report we have investigated the effects of HDAC inhibitors on the expression of lipid metabolizing enzymes, COX-1, COX-2, and 15-LO-1, in human brain cell lines. We report for the first time that HDAC inhibitors induce only COX-1 expression, not COX-2, in normal human astrocyte cells and glioma cell lines
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