Pharmacologic Unmasking of Epigenetically Silenced Tumor Suppressor Genes in Esophageal Squamous Cell Carcinoma

Cancer Cell. 2002 Dec;2(6):485-95. doi: 10.1016/s1535-6108(02)00215-5.

Abstract

We performed a comprehensive survey of commonly inactivated tumor suppressor genes in esophageal squamous cell carcinoma (ESCC) based on functional reactivation of epigenetically silenced tumor suppressor genes by 5-aza-2'-deoxycytidine and trichostatin A using microarrays containing 12599 genes. Among 58 genes identified by this approach, 44 (76%) harbored dense CpG islands in the promoter regions. Thirteen of twenty-two tested gene promoters were methylated in cell lines, and ten in primary ESCC accompanied by silencing at the mRNA level. Potent growth suppressive activity of three genes including CRIP-1, Apolipoprotein D, and Neuromedin U in ESCC cells was demonstrated by colony focus assays. Pharmacologic reversal of epigenetic silencing is a powerful approach for comprehensive identification of tumor suppressor genes in human cancers.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Azacitidine / analogs & derivatives*
  • Azacitidine / pharmacology
  • Base Sequence
  • Carcinoma, Squamous Cell / genetics*
  • CpG Islands / genetics
  • DNA Methylation*
  • Decitabine
  • Down-Regulation
  • Enzyme Inhibitors / pharmacology
  • Esophageal Neoplasms / genetics
  • Gene Expression Regulation, Neoplastic*
  • Gene Silencing* / drug effects
  • Genes, Tumor Suppressor* / drug effects
  • Humans
  • Hydroxamic Acids / pharmacology
  • Molecular Sequence Data
  • Oligonucleotide Array Sequence Analysis
  • Promoter Regions, Genetic
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured

Substances

  • Enzyme Inhibitors
  • Hydroxamic Acids
  • trichostatin A
  • Decitabine
  • Azacitidine