Abstract
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.
Highlights
Mitogen inducible gene 6 (MIG-6) is an immediate early response gene that is expressed in various tissues and plays a critical role in many pathophysiological states [1]
To determine whether MIG-6 expression was affected by epigenetic alteration, we first identified human cancer cell lines in which its promoter is likely affected by methylation or histone deacetylation
We found that trichostatin A (TSA) treatment significantly increased the amount of MIG-6 protein in the lung cancer cell lines, but not in the melanoma lines (Figure 2A)
Summary
Mitogen inducible gene 6 (MIG-6) ( known as gene 33, ERRFI1, or RALT) is an immediate early response gene that is expressed in various tissues and plays a critical role in many pathophysiological states [1]. As a cytoplasmic scaffolding adaptor, MIG-6 has several important protein-protein interaction motifs that may mediate interaction with signaling molecules downstream of receptor tyrosine kinases (RTKs) [2]. One of the most prominent roles of MIG-6 in regulating signal transduction comes from its ability to directly interact with epidermal growth factor receptor (EGFR) and other ErbB family members, inhibiting their phosphorylation and downstream signaling in a negative feedback fashion [6,7,8,9]. MIG-6 can be induced by hepatocyte growth factor (HGF) and functions as a negative feedback regulator of HGF-MET signaling [10,11], indicating that it has broad role as a signal checkpoint for modulating activated RTK pathways in a timely manner
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