Tumor necrosis factor alpha negatively regulates the expression of the carcinoma-associated antigen epithelial cell adhesion molecule

BACKGROUND. The epithelial cell adhesion molecule (EpCAM) is a homophilic a nd Ca2+ independent adhesion molecule that is expressed de novo in squamous cell carcinoma (SCC) but is absent in the majority of healthy squamous epi thelia. EpCAM expression correlates with cell proliferation and dedifferent iation along with a progression in tumorigenicity. To date, nothing is know n about the molecular mechanisms responsible for the regulation of the EpCA M gene. METHODS. The authors analyzed the regulation of a fragment of the EpCAM pro moter. RESULTS. The analyzed fragment has significant activity in EpCAM positive c ells, and it is regulated negatively by tumor necrosis factor alpha (TNF al pha). This negative regulation results in diminished mRNA expression and in the down-regulation of EpCAM protein at the cell surface in SCC cells. Bot h effects can be mimicked by the treatment of cells with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). TNF alpha -induced inhibition o f the EpCAM expression is mediated by TNF receptor 1 through the TNF recept or-associated death domain protein (TRADD) and by the activation of nuclear factor kappaB (NF-kappaB), and it can be blocked by dominant-negative vari ants of TRADD and the NF-kappaB inhibitor, I kappaB. The authors provide fu rther evidence that NF-kappaB represses EpCAM expression by competing for t he transcriptional coactivator p300/CREB binding protein (p300/CBP). CONCLUSIONS. The current results provide the first insights into the regula tion of EpCAM expression, which is regulated negatively by TNF alpha and TP A through the activation of NF-kappaB. The repression may rely on the compe tition of NF-kappaB for p300/CBP histone acetyl transferase activity, becau se the overexpression of p300 reverts TNF alpha effects. Cancer 2001;92:620 -8. (C) 2001 American Cancer Society.