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
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Acetylation
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Adaptor Proteins, Signal Transducing
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Adenocarcinoma / genetics
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Adenocarcinoma / pathology
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Base Sequence
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Bronchi / metabolism
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Carcinoma, Non-Small-Cell Lung / genetics*
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Carcinoma, Non-Small-Cell Lung / pathology
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Carcinoma, Squamous Cell / genetics
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Carcinoma, Squamous Cell / pathology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Chromatin Assembly and Disassembly
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Chromatin Immunoprecipitation
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DNA Methylation / drug effects
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation, Neoplastic / physiology*
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Histone Deacetylase Inhibitors
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Histone Deacetylases / metabolism
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Histones / metabolism
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Humans
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Hydroxamic Acids / pharmacology
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Intracellular Signaling Peptides and Proteins / genetics*
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Lung / metabolism
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Lung Neoplasms / genetics*
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Lung Neoplasms / pathology
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Molecular Sequence Data
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Promoter Regions, Genetic / genetics
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Transcription, Genetic
Substances
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Adaptor Proteins, Signal Transducing
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DOK4 protein, human
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Enzyme Inhibitors
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Histone Deacetylase Inhibitors
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Histones
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Hydroxamic Acids
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Intracellular Signaling Peptides and Proteins
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RNA, Messenger
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trichostatin A
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Histone Deacetylases