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Suppressor Gene in Human Colon Cancer as a Differentiation-related , Putative Metastatic Drg-1 Updated

A gene related to cell differentiation was identified by differential display as a candidate suppressor of metastases in colon cancer. This gene, with a full-length cDNA of 3 kb, is expressed in normal colon and primary colon cancer tissues and cell lines but not in their metastatic counterparts. A GenBank search found that it is identical to a recently cloned gene, differentiation-related gene-1(Drg-1), isolated from differentiated HT-29 colon cancer cells. Stable transfection of the SW620 metastatic colon cancer cell line with Drg-1 cDNA induced morphological changes consistent with differentiation and up-regulated the expression of several colonic epithelial cell differentiation markers (alkaline phosphatase, carcinoembryonic antigen, and E-cadherin). Moreover, the expression ofDrg-1 is controlled by several known cell differentiation reagents, such as ligands of peroxisome proliferator-activated receptor g (troglitazone and BRL46593) and of retinoid X receptor (LG268), and histone deacetylase inhibitors (trichostatin A, suberoylanilide hydroxamic acid, and tributyrin). A synergistic induction of Drg-1 expression was seen with the combination of tributyrin and a low dose of 5*-aza-2*-dexoycytidine (100 nM), an inhibitor of DNA methylation. Functional studies revealed that overexpression ofDrg-1 in metastatic colon cancer cells reducedin vitro invasion through Matrigel and suppressedin vivo liver metastases in nude mice. We propose thatDrg-1 suppresses colon cancer metastasis by inducing colon cancer cell differentiation and partially reversing the metastatic phenotype.