Down‐regulation of desmoglein‐2 in colonic epithelial cells suppresses proliferation and reduces tumor growth via a desmocollin‐2‐dependent mechanism

Expression of the desmosomal cadherins desmoglein‐2 (Dsg2) and desmocollin‐2 (Dsc2) is altered in epithelial cancers, and we have shown that loss of Dsc2 in colonic epithelial cell lines enhances proliferation and tumor formation, thus providing evidence of a tumor suppressor function for Dsc2. To determine if loss of Dsg2 has similar effects, we used shRNA to down‐regulate Dsg2 expression in colonic epithelial cell lines. Interestingly, loss of Dsg2 decreased cell proliferation and inhibited xenograft tumor formation in mice. Furthermore, down‐regulation of Dsg2 in a Dsc2‐negative epithelial cell line had no effect on proliferation or tumor growth, indicating that Dsc2 may promote growth suppression following loss of Dsg2. To examine whether Dsc2 contributes to growth suppression in Dsg2‐deficient cells, we assessed the effect of Dsg2 loss on Dsc2 expression. Our results show that Dsg2‐deficient cells have increased Dsc2 protein levels compared to controls, suggesting that compensatory Dsc2 up‐regulation may mediate growth suppression. Consistent with this notion, siRNA knockdown of Dsc2 restored proliferation in Dsg2‐deficient colonic epithelial cell lines. Taken together, our data demonstrate that, unlike Dsc2, loss of Dsg2 reduces cell growth and inhibits tumor formation in vivo. Thus, anti‐Dsg2‐targeted therapies may be useful for inhibiting growth of tumors expressing both Dsc2 and Dsg2. This work was supported by CCFA Fellowship and AGA Research Scholar Awards (PN) and NIH grants DK61379 (CP), DK55679 and DK59888 (AN).