MeCP2 and promoter methylation cooperatively regulate E-cadherin gene expression in colorectal carcinoma.

Reduced expression of E-cadherin (E-cad) owing to aberrant 5'CpG island hypermethylation has been regarded as one of the main molecular events involved in the dysfunction of the cell-cell adhesion system. The molecular mechanisms providing diversity and heterogeneity of E-cad expression in colorectal carcinoma were explored. In 29 cases of colorectal carcinoma in Indonesia, the expression of E-cad was analyzed by immunohistochemical staining, the methylation status of the E-cad promoter was determined by methylation-specific PCR, and the expression of methyl-CpG-binding protein (MeCP) 2 was studied by in situ hybridization. E-cad expression was strong, and no methylation was observed in normal colon mucosa and most of the well-differentiated adenocarcinoma. In contrast, both signet-ring cell carcinoma and mucinous adenocarcinoma showed fully methylated patterns and strong MeCP2 expression. In moderately- and poorly-differentiated adenocarcinomas, however, E-cad expression was rather heterogeneous, especially at the front of invasion and in the dissociated areas, where loss of MeCP2 expression correlated with E-cad reexpression even in the presence of E-cad promoter methylation. We conclude that both CpG methylation of the E-cad promoter and significant MeCP2 expression cooperatively and epigenetically regulate E-cad expression in colorectal cancer.