Drg-1 as a differentiation-related, putative metastatic suppressor gene inhuman colon cancer

A gene related to cell differentiation was identified by differential displ ay 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, differ entiation-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-l cDNA induced morphological changes consistent with differe ntiation and up-regulated the expression of several colonic epithelial cell differentiation markers (alkaline phosphatase, carcinoembryonic antigen, a nd E-cadherin), Moreover, the expression of Drg-1 is controlled by several known cell differentiation reagents, such as ligands of peroxisome prolifer ator-activated receptor gamma (troglitazone and BRL46593) and of retinoid X receptor (LG268), and histone deacetylase inhibitors (trichostatin A, sube roylanilide hydroxamic acid, and tributyrin), A synergistic induction of Dr g-1 expression was seen with the combination of tributyrin and a low dose o f 5'-aza-2'-dexoycytidine (100 nM), an inhibitor-of DNA methylation. Functi onal studies revealed that overexpression of Drg-1 in metastatic colon canc er cells reduced ill vitro invasion through Matrigel and suppressed in vivo liver metastases in nude mice. We propose that Drg-1 suppresses colon canc er metastasis by inducing colon cancer cell differentiation and partially r eversing the metastatic phenotype.