Nonsteroidal anti-inflammatory drug-activated gene (NAG-1/GDF15) expression is increased by the histone deacetylase inhibitor trichostatin A

J Biol Chem. 2008 Nov 28;283(48):33129-37. doi: 10.1074/jbc.M805248200. Epub 2008 Sep 17.

Abstract

Nonsteroidal anti-inflammatory drug-activated gene (NAG-1) is a putative tumor suppressor whose expression can be increased by drug treatment. Glioblastoma is the most common central nervous system tumor, is associated with high morbidity and mortality, and responds poorly to surgical, chemical, and radiation therapy. The histone deacetylase inhibitors are under current consideration as therapeutic agents in treating glioblastoma. We investigated whether trichostatin A (TSA) would alter the expression of NAG-1 in glioblastoma cells. The DNA demethylating agent 5-aza-dC did not increase NAG-1 expression, but TSA up-regulated NAG-1 expression and acted synergistically with 5-aza-dC to induce NAG-1 expression. TSA indirectly increases NAG-1 promoter activity and increases NAG-1 mRNA and protein expression in the T98G human glioblastoma cell line. TSA also increases the expression of transcription factors Sp-1 and Egr-1. Small interfering RNA experiments link NAG-1 expression to apoptosis induced by TSA. Reporter gene assays, specific inhibition by small interfering RNA transfections, and chromatin immunoprecipitation assays indicate that Egr-1 and Sp-1 mediate TSA-induced NAG-1 expression. TSA also increases the stability of NAG-1 mRNA. TSA-induced NAG-1 expression involves multiple mechanisms at the transcriptional and post-transcriptional levels.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Azacitidine / analogs & derivatives
  • Azacitidine / pharmacology
  • Cell Line, Tumor
  • Decitabine
  • Early Growth Response Protein 1 / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Glioblastoma / metabolism*
  • Growth Differentiation Factor 15 / antagonists & inhibitors
  • Growth Differentiation Factor 15 / biosynthesis*
  • Histone Deacetylase Inhibitors*
  • Humans
  • Hydroxamic Acids / pharmacology*
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / biosynthesis*
  • RNA, Messenger / biosynthesis
  • RNA, Neoplasm / biosynthesis
  • RNA, Small Interfering / pharmacology
  • Sp1 Transcription Factor / metabolism
  • Up-Regulation / drug effects

Substances

  • EGR1 protein, human
  • Early Growth Response Protein 1
  • Enzyme Inhibitors
  • GDF15 protein, human
  • Growth Differentiation Factor 15
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Neoplasm Proteins
  • RNA, Messenger
  • RNA, Neoplasm
  • RNA, Small Interfering
  • Sp1 Transcription Factor
  • trichostatin A
  • Decitabine
  • Azacitidine