Epithelial cell adhesion molecule (EpCAM) (CD326) is a surface glycoprotein 
expressed by invasive carcinomas and some epithelia. Herein, we report that 
EpCAM regulates the composition and function of tight junctions (TJ). EpCAM 
accumulated on the lateral interfaces of human colon carcinoma and normal 
intestinal epithelial cells but did not co-localize with TJ. Knockdown of EpCAM 
in T84 and Caco-2 cells using shRNAs led to changes in morphology and 
adhesiveness. TJ formed readily after EpCAM knockdown; the acquisition of 
trans-epithelial electroresistance was enhanced, and TJ showed increased 
resistance to disruption by calcium chelation. Preparative immunoprecipitation 
demonstrated that EpCAM bound tightly to claudin-7. Co-immunoprecipitation 
documented associations of EpCAM with claudin-7 and claudin-1 but not claudin-2 
or claudin-4. Claudin-1 associated with claudin-7 in co-transfection 
experiments, and claudin-7 was required for association of claudin-1 with EpCAM. 
EpCAM knockdown resulted in decreases in claudin-7 and claudin-1 proteins that 
were reversed with lysosome inhibitors. Immunofluorescence microscopy revealed 
that claudin-7 and claudin-1 continually trafficked into lysosomes. Although 
EpCAM knockdown decreased claudin-1 and claudin-7 protein levels overall, 
accumulations of claudin-1 and claudin-7 in TJ increased. Physical interactions 
between EpCAM and claudins were required for claudin stabilization. These 
findings suggest that EpCAM modulates adhesion and TJ function by regulating 
intracellular localization and degradation of selected claudins.