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

Inhibitors of DNA methyltransferase, typified by 5-aza-2'-deoxycytidine (5- Aza-CdR), induce the expression of genes transcriptionally down-regulated b y de novo methylation in tumor cells. We utilized gene expression microarra ys to examine the effects of 5-Aza-CdR treatment in HT29 colon adenocarcino ma cells. This analysis revealed the induction of a set of genes that impli cated 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-alpha. These observ ations implicate the induction of the IFN-response pathway as a major cellu lar response to 5-Aza-CdR and suggests that the expression of STATs 1, 2, a nd 3 can be regulated by DNA methylation. Consistent with STAT's limiting c ell responsiveness to IFN, we found that 5-Aza-CdR treatment sensitized HT2 9 cells to growth inhibition by exogenous IFN-alpha 2a. indicating that 5-A za-CdR should be investigated as a potentiator of IFN responsiveness in cer tain IFN-resistant tumors.