Limited Gene Activation in Tumor and Normal Epithelial Cells Treated with the DNA Methyltransferase Inhibitor 5-Aza-2′-deoxycytidine

Adam R Karpf, Amy W. Lasek, Ted O. Ririe, Adrianne N. Hanks, Douglas Grossman, David A. Jones

Research output: Contribution to journalArticle

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Abstract

It remains unclear to what extent drugs targeting transcriptional repressor complexes affect global gene expression in cells derived from target and nontarget human tissues. To address this question, we used genome-wide expression analysis using microarrays to analyze the response of three tumor and one normal epithelial cell line to treatment with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (5-aza-CdR). Notably, we found that 5-aza-CdR treatment induced a limited number of genes (mean, 0.67%; range, 0.17-1.8% of 25,940 genes screened) in each cell line tested. The majority of the gene expression changes that followed 5-aza-CdR treatment were conserved in tumor and normal cells, including genes that function in cell proliferation, differentiation, immune presentation, and cytokine signaling. In contrast, 5-aza-CdR treatment induced the expression of cancer-testis class tumor antigens only in tumor cell lines. To explain this tissue-specific response, we analyzed the mechanism of transcriptional regulation of the prototype member of this tumor antigen gene family, MAGE-1. Taken from our analysis of MAGE-1 gene regulation, we propose that 5-aza-CdR-mediated gene activation has two distinct requirements: 1) the reversal of promoter hypermethylation, and 2) the presence of transcriptional activators competent for the activation of hypomethylated target promoters. This latter requirement for gene activation by 5-aza-CdR is probably mediated by sequence-specific transcription factors and may account for the limited number of human genes induced by 5-aza-CdR treatment. This revised model for gene activation by 5-aza-CdR has important implications for the use of DNA methyltransferase inhibitors in clinical settings.

Original languageEnglish (US)
Pages (from-to)18-27
Number of pages10
JournalMolecular pharmacology
Volume65
Issue number1
DOIs
StatePublished - Jan 1 2004

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decitabine
Methyltransferases
Transcriptional Activation
Epithelial Cells
DNA
Genes
Neoplasms
Neoplasm Antigens
Gene Expression
Cell Line
Testicular Neoplasms
Therapeutics
Drug Delivery Systems
Microarray Analysis
Tumor Cell Line
Cell Differentiation
Transcription Factors
Cell Proliferation
Genome
Cytokines

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Limited Gene Activation in Tumor and Normal Epithelial Cells Treated with the DNA Methyltransferase Inhibitor 5-Aza-2′-deoxycytidine. / Karpf, Adam R; Lasek, Amy W.; Ririe, Ted O.; Hanks, Adrianne N.; Grossman, Douglas; Jones, David A.

In: Molecular pharmacology, Vol. 65, No. 1, 01.01.2004, p. 18-27.

Research output: Contribution to journalArticle

Karpf, Adam R ; Lasek, Amy W. ; Ririe, Ted O. ; Hanks, Adrianne N. ; Grossman, Douglas ; Jones, David A. / Limited Gene Activation in Tumor and Normal Epithelial Cells Treated with the DNA Methyltransferase Inhibitor 5-Aza-2′-deoxycytidine. In: Molecular pharmacology. 2004 ; Vol. 65, No. 1. pp. 18-27.
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