Aberrant methylation and histone deacetylation of cyclooxygenase 2 in gastric cancer

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Abstract
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.