We performed DNA microarray analyses on samples derived from A427 lung cancer and M14 melanoma cells treated with 5- aza-dC and/or TSA. Figure 9A shows the genes displaying an expression pattern similar to that of MIG-6 in response to either BTZ043 5-aza-dC or TSA treatment. Another group of genes appeared to be down-regulated, the opposite of MIG-6 expression. Among the up-regulated genes were those coding for transcription factors such as EGR1 and STAT1, the MIG-6-inducible gene HBEGF, and genes coding for NSC348884 histone proteins. Even though those genes were differentially expressed in A427 and M14 cells, further analyses revealed that EGR1 displayed an expression pattern similar to that of MIG-6 across the four lung cancer cell lines and five melanoma lines. Thus, MIG-6 was not the only gene differentially regulated in the lung cancer and melanoma cells. Perhaps there are tissue-specific factors that respond differently to 5-aza-dC and TSA, leading to differential induction of MIG-6 and EGR1 in lung cancer and melanoma cells. MIG-6, a tumor suppressor gene, has been found downregulated in many human cancers. To determine if downregulation of MIG-6 expression was affected by epigenetic modification in its promoter, we treated lung cancer and melanoma cell lines with inhibitors of methylation and histone deacetylation and then determined how those inhibitors influenced MIG-6 expression. Intriguingly, we found that DNMT inhibitor 5- aza-dC specifically induced MIG-6 expression in melanoma cells but not in lung cancer cells, while the HDAC inhibitor TSA induced the reverse pattern. Despite both inductions being regulated at transcriptional level, we were surprised to find that the MIG-6 promoter was neither hypermethylated nor directly affected by histone deacetylation, indicating that an indirect mechanism might be responsible for differential induction. In fact, 5-aza-dC has also been reported to induce the expression of several other genes whose promoters are not directly affected by methylation in leukemia cells, suggesting that 5-aza-dC might have a broader influence on regulating gene expression via a methylation-independent manner. Many DNMT inhibitors and HDAC inhibitors are currently in clinical trials