Transcriptional regulation of IRS5/DOK4 expression in non-small-cell lung cancer cells

Clin Lung Cancer. 2008 Nov;9(6):367-74. doi: 10.3816/CLC.2008.n.053.

Abstract

The insulin-receptor substrate family plays important roles in cellular growth, signaling, and survival. Two new members of this family have recently been isolated: IRS5/Dok4 and IRS6/Dok5. This study examines the expression of IRS5/DOK4 in a panel of lung cancer cell lines and tumor specimens. The results demonstrate that expression of IRS5/DOK4 is frequently altered with both elevated and decreased expression in non-small-cell lung cancer (NSCLC) tumor specimens. The altered expression of IRS5/DOK4 observed in tumor samples is not due to aberrant methylation. In vitro cell culture studies demonstrate that treatment of NSCLC cell lines with the histone deacetylase inhibitor trichostatin A (TSA) upregulates IRS5/DOK4. This finding indicates that expression is regulated epigenetically at the level of chromatin remodeling. Chromatin immunoprecipitation experiments confirm that the IRS5/DOK4 promoter has enhanced histone hyperacetylation following treatments with TSA. Finally, hypoxia was demonstrated to downregulate IRS5/DOK4 expression. This expression was restored by TSA. The clinical relevance of altered IRS5/DOK4 expression in NSCLC requires further evaluation.

MeSH terms

  • Acetylation
  • Adaptor Proteins, Signal Transducing
  • Adenocarcinoma / genetics
  • Adenocarcinoma / pathology
  • Base Sequence
  • Bronchi / metabolism
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chromatin Assembly and Disassembly
  • Chromatin Immunoprecipitation
  • DNA Methylation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation, Neoplastic / physiology*
  • Histone Deacetylase Inhibitors
  • Histone Deacetylases / metabolism
  • Histones / metabolism
  • Humans
  • Hydroxamic Acids / pharmacology
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Lung / metabolism
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Molecular Sequence Data
  • Promoter Regions, Genetic / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription, Genetic

Substances

  • Adaptor Proteins, Signal Transducing
  • DOK4 protein, human
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Histones
  • Hydroxamic Acids
  • Intracellular Signaling Peptides and Proteins
  • RNA, Messenger
  • trichostatin A
  • Histone Deacetylases