Epigenetic silencing is one of the mechanisms leading to inactivation of a tumor 
suppressor gene, either by DNA methylation or histone modification in a promoter 
regulatory region. Mitogen inducible gene 6 (MIG-6), mainly known as a negative 
feedback inhibitor of the epidermal growth factor receptor (EGFR) family, is a 
tumor suppressor gene that is associated with many human cancers. To determine 
if MIG-6 is inactivated by epigenetic alteration, we identified a group of human 
lung cancer and melanoma cell lines in which its expression is either low or 
undetectable and studied the effects of methylation and of histone deacetylation 
on its expression. The DNA methyltransferase (DNMT) inhibitor 
5-aza-2'-deoxycytidine (5-aza-dC) induced MIG-6 expression in melanoma cell 
lines but little in lung cancer lines. By contrast, the histone deacetylase 
(HDAC) inhibitor trichostatin A (TSA) induced MIG-6 expression in lung cancer 
lines but had little effect in melanoma lines. However, the MIG-6 promoter 
itself did not appear to be directly affected by either methylation or histone 
deacetylation, indicating an indirect regulatory mechanism. Luciferase reporter 
assays revealed that a short segment of exon 1 in the MIG-6 gene is responsible 
for TSA response in the lung cancer cells; thus, the MIG-6 gene can be 
epigenetically silenced through an indirect mechanism without having a physical 
alteration in its promoter. Furthermore, our data also suggest that MIG-6 gene 
expression is differentially regulated in lung cancer and melanoma.