Epigenetic regulation of metastasis-related genes in gastric cancer

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Levels of protein products of 76 metastasis-related genes were examined in COLQ320 (colon cancer), MKN28 (gastric cancer), SRC29 (renal cancer), U937 (leukemia), and JEC6 (intestinal epithelium) cell lines treated with or without deoxyazacytidine (AZA) and/or trichostatine A (TSA), Alteration of protein levels by treatment with AZA and/or TSA was found in RAGE, IL-8, E-cadherin, MMP-9, MLH1 , Rho, and c-MET in cell type-specific and gene-specific manners. Next, epigenetics of RAGE and the ligand HMG1 were examined. RAGE-negative MKN45 gastric cancer cells showed DNA methylation at the Sp-1 site in the RAGE gene promoter. HMG1, originally reported as a chromatin protein, was translocated from nucleus to cytoplasm through histone acetylation by TSA treatment. Simplifying the complicating cancer epigenetics, we analyzed the mucosa adjacent to colon cancer in the athymic mice model. The mucosa showed hypoacetylation of histone H4, repression of p53 and VHL, which were associated with retention of HlF-1α protein and induction of VEGF in the mucosa. The mucosa also showed repression of p16, MLH1, and MGMT by means of promoter hypermethylation of the genes. In in vitro examination, growth factors played a role in repression of these genes.