Transcriptional regulation of cyclooxygenase-1 by histone deacetylase inhibitors in normal human astrocyte cells

J Biol Chem. 2002 May 10;277(19):16823-30. doi: 10.1074/jbc.M200527200. Epub 2002 Mar 4.

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.

MeSH terms

  • Acetylation
  • Arachidonic Acid / pharmacology
  • Astrocytes / enzymology*
  • Astrocytes / metabolism
  • Binding Sites
  • Blotting, Northern
  • Cell Nucleus / metabolism
  • Cyclooxygenase 1
  • DNA Mutational Analysis
  • DNA, Complementary / metabolism
  • Dinoprostone / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Enzyme-Linked Immunosorbent Assay
  • Glioma / metabolism
  • Histone Deacetylase Inhibitors*
  • Histones / metabolism
  • Humans
  • Hydroxamic Acids / pharmacology
  • Immunoblotting
  • Isoenzymes / genetics*
  • Isoenzymes / metabolism*
  • Membrane Proteins
  • Mutation
  • Neuroglia / metabolism
  • Oligonucleotides / pharmacology
  • Promoter Regions, Genetic
  • Prostaglandin-Endoperoxide Synthases / genetics*
  • Prostaglandin-Endoperoxide Synthases / metabolism*
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sp1 Transcription Factor / metabolism
  • Time Factors
  • Transcription, Genetic*
  • Tumor Cells, Cultured
  • Up-Regulation

Substances

  • DNA, Complementary
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Histones
  • Hydroxamic Acids
  • Isoenzymes
  • Membrane Proteins
  • Oligonucleotides
  • RNA, Messenger
  • Sp1 Transcription Factor
  • Arachidonic Acid
  • trichostatin A
  • Cyclooxygenase 1
  • PTGS1 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Dinoprostone