Inhibition of DNA methyltransferase stimulates the expression of signal transducer and activator of transcription 1, 2, and 3 genes in colon tumor cells

• DOI: 10.1073/pnas.96.24.14007
• Publication Date: 2002-07-26T14:35:07Z
• Authors: Adam R. Karpf; Peter W. Peterson; Joseph T. Rawlins; Brian K. Dalley; Qian Yang; Hans Albertsen; David A. Jones
• Keywords: Cell Nucleus; 0301 basic medicine; Antimetabolites, Antineoplastic; Interferon-alpha; Antineoplastic Agents; Interferon-beta; Interferon alpha-2; Decitabine; Recombinant Proteins; DNA-Binding Proteins; Gene Expression Regulation, Neoplastic; Interferon-gamma; 03 medical and health sciences; STAT1 Transcription Factor; Colonic Neoplasms; Azacitidine; Humans; Interferons; Enzyme Inhibitors; DNA Modification Methylases; HT29 Cells; Cell Division

Inhibitors of DNA methyltransferase, typified by 5-aza-2′-deoxycytidine (5-Aza-CdR), induce the expression of genes transcriptionally down-regulated byde novomethylation in tumor cells. We utilized gene expression microarrays to examine the effects of 5-Aza-CdR treatment in HT29 colon adenocarcinoma cells. This analysis revealed the induction of a set of genes that implicated IFN signaling in the HT29 cellular response to 5-Aza-CdR. Subsequent investigations revealed that the induction of this gene set correlates with the induction of signal transducer and activator of transcription (STAT) 1, 2, and 3 genes and their activation by endogenous IFN-α. These observations implicate the induction of the IFN-response pathway as a major cellular response to 5-Aza-CdR and suggests that the expression of STATs 1, 2, and 3 can be regulated by DNA methylation. Consistent with STAT’s limiting cell responsiveness to IFN, we found that 5-Aza-CdR treatment sensitized HT29 cells to growth inhibition by exogenous IFN-α2a, indicating that 5-Aza-CdR should be investigated as a potentiator of IFN responsiveness in certain IFN-resistant tumors.