Aberrant methylation and histone deacetylation of cyclooxygenase 2 in gastric cancer.
Cyclooxygenase 2 plays a critical role in the development of gastrointestinal cancers in both human and animal models. About 80% of the gastric cancer showed a high level of expression of cyclooxygenase 2, but a subset of cases do not express without unknown reason. Aberrant methylation of CpG island of COX-2 was examined by using a series of gastric cancer cell lines and primary gastric cancers. Two out of 8 cell lines (25%) and 11 out of 93 (12%) primary cancers showed aberrant methylation of the 5' region of COX-2. Methylation of COX-2 was closely associated with loss of expression and treatment of methylation inhibitor, 5-deoxy-2'-azacytidine restored the expression of COX-2. A combined treatment of 5-deoxy-2'-azacytidine and a histone deacetylese inhibitor, trichostatin A, restored re-expression of the gene synergistically and chromatin immunoprecipitation analysis revealed that histone of methylated COX-2 promoter is deacetylated, indicating the role of cytosine methylation and histone deacetylation in the silencing of the gene. These results indicate that a subset of gastric cancer with COX-2 methylation evolves through the pathway that is independent of COX-2 expression and that COX-2 inhibitor may not be useful to induce apoptosis in these cases.
Kikuchi
Takefumi
T
First Department of Internal Medicine, Sapporo Medical University, S-1, W-16, Chuo-ku, Sapporo 060-8543, Japan.
Itoh
Fumio
F
Toyota
Minoru
M
Suzuki
Hiromu
H
Yamamoto
Hiroyuki
H
Fujita
Masahiro
M
Hosokawa
Masao
M
Imai
Kohzoh
K
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051546:Cyclooxygenase 2; D003596:Cytosine / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D019175:DNA Methylation; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005753:Gastric Mucosa / Q000378:metabolism; D020868:Gene Silencing; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000096:biosynthesis*; D008565:Membrane Proteins; D008745:Methylation; D018807:Polymorphism, Single-Stranded Conformational; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000378:metabolism*; D013447:Sulfites / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007527:Isoenzymes; D008565:Membrane Proteins; D013447:Sulfites; C012589:trichostatin A; D000077209:Decitabine; D003596:Cytosine; D004247:DNA; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D006655:Histone Deacetylases; D001374:Azacitidine