Epigenetic control of MAGE gene expression by the KIT tyrosine kinase.
The Class I MAGE proteins include the MAGE-A, MAGE-B, and MAGE-C antigens, which are normally expressed only in male germ cells but may be aberrantly expressed in melanomas and other tumors. It is known that MAGE gene expression is epigenetically repressed by promoter region methylation in most cells but factors controlling MAGE gene promoter methylation have not been identified. Using transcript microarray analysis and immunoblotting we found that MAGE-A and MAGE-C mRNA and protein are selectively downregulated by pharmacologic inhibition of KIT in KIT-dependent mast cell lines. Methylation-specific polymerase chain reaction studies showed that the MAGE-A3 and MAGE-C2 gene promoter regions were de-methylated in the presence of activated KIT but became methylated on inhibition of KIT, consistent with the downregulation of mRNA and protein. This is early evidence of a tyrosine kinase affecting MAGE gene promoter region methylation and expression, and represents early evidence of a tyrosine kinase in the epigenetic control of gene expression. MAGE proteins suppress apoptosis and promote tumor survival, and are novel targets for functional manipulation and immunotherapy. Understanding the factors controlling MAGE gene expression may allow more effective therapeutic strategies targeting MAGE antigens.
Yang
Bing
B
Department of Dermatology, University of Wisconsin Medical School, Madison, Wisconsin 53715, USA. byang@dermatology.wisc.edu
Wu
Jianqiang
J
Maddodi
Nityanand
N
Ma
Yongsheng
Y
Setaluri
Vijayasaradhi
V
Longley
B Jack
BJ
D000951:Antigens, Neoplasm / Q000378:metabolism / Q000502:physiology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001549:Benzamides; D045744:Cell Line, Tumor; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000068877:Imatinib Mesylate; D009363:Neoplasm Proteins / Q000378:metabolism / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D010879:Piperazines / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D001549:Benzamides; C072013:MAGEA3 protein, human; C405429:MAGEC2 protein, human; D009363:Neoplasm Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit