DNA methylation and histone deacetylation associated with silencing DAP kinase gene expression in colorectal and gastric cancers.
Death-associated protein kinase is a positive regulator of programmed cell death induced by interferon gamma. To investigate the role of epigenetic inactivation of death-associated protein kinase in gastrointestinal cancer, we examined the methylation status of the 5' CpG island of the death-associated protein kinase gene. Methylation of the 5' CpG island was detected in 3 of 9 colorectal and 3 of 17 gastric cancer cell lines, while among primary tumours, it was detected in 4 of 28 (14%) colorectal and 4 of 27 (15%) gastric cancers. By contrast, methylation of the edge of the CpG island was detected in virtually every sample examined. Death-associated protein kinase expression was diminished in four cell lines that showed dense methylation of the 5' CpG island, and treatment with 5-aza-2'-deoxycitidine, a methyltransferase inhibitor, restored gene expression. Acetylation of histones H3 and H4 in the 5' region of the gene was assessed by chromatin immunoprecipitation and was found to correlate directly with gene expression and inversely with DNA methylation. Thus, aberrant DNA methylation and histone deacetylation of the 5' CpG island, but not the edge of the CpG island, appears to play a key role in silencing death-associated protein kinase expression in gastrointestinal malignancies.
Satoh
A
A
First Department of Internal Medicine, Sapporo Medical University, S-1, W-16, Chuo-ku, Sapporo 060-8543, Japan.
Toyota
M
M
Itoh
F
F
Kikuchi
T
T
Obata
T
T
Sasaki
Y
Y
Suzuki
H
H
Yawata
A
A
Kusano
M
M
Fujita
M
M
Hosokawa
M
M
Yanagihara
K
K
Tokino
T
T
Imai
K
K
D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics*; D019175:DNA Methylation; D017931:DNA Primers; D064550:Death-Associated Protein Kinases; D015226:Dinucleoside Phosphates / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D016133:Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000201:enzymology / Q000235:genetics*; D014407:Tumor Cells, Cultured
D051017:Apoptosis Regulatory Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D017931:DNA Primers; D064550:Death-Associated Protein Kinases; D015226:Dinucleoside Phosphates; D006655:Histone Deacetylases; C015772:CpG dinucleotide