Transcriptional regulation of cyclooxygenase-1 by histone deacetylase inhibitors in normal human astrocyte cells.
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.
Taniura
Seijiro
S
Laboratory of Molecular Carcinogenesis, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Kamitani
Hideki
H
Watanabe
Takashi
T
Eling
Thomas E
TE
D000107:Acetylation; D016718:Arachidonic Acid / Q000494:pharmacology; D001253:Astrocytes / Q000201:enzymology* / Q000378:metabolism; D001665:Binding Sites; D015152:Blotting, Northern; D002467:Cell Nucleus / Q000378:metabolism; D051545:Cyclooxygenase 1; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005910:Glioma / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D015151:Immunoblotting; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism*; D008565:Membrane Proteins; D009154:Mutation; D009457:Neuroglia / Q000378:metabolism; D009841:Oligonucleotides / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016329:Sp1 Transcription Factor / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007527:Isoenzymes; D008565:Membrane Proteins; D009841:Oligonucleotides; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor; D016718:Arachidonic Acid; C012589:trichostatin A; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone