Cancer-type regulation of MIG-6 expression by inhibitors of methylation and histone deacetylation.
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.
Laboratory of Molecular Oncology, Van Andel Research Institute, Grand Rapids, Michigan, United States of America. YuWen.Zhang@vai.org
Yu-Wen
YW
Zhang
Ben
B
Staal
Karl J
KJ
Dykema
Kyle A
KA
Furge
George F
GF
Vande Woude
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D018899:CpG Islands / Q000235:genetics; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors*; D017931:DNA Primers / Q000235:genetics; D000077209:Decitabine; D044127:Epigenesis, Genetic / Q000187:drug effects* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008156:Luciferases; D046228:Microarray Analysis; D008969:Molecular Sequence Data; D010957:Plasmids / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D017931:DNA Primers; C484017:ERRFI1 protein, human; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D025521:Tumor Suppressor Proteins; C012589:trichostatin A; D000077209:Decitabine; D008156:Luciferases; D015254:DNA Modification Methylases; D001374:Azacitidine