The Role of E-cadherin N-glycans in Oral Cancer

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DESCRIPTION (provided by applicant): Oral cancer constitutes 1 of the most pernicious cancers with only a 5-year predicted survival following diagnosis. Our research proposes to elucidate some of the underlying causes of oral cancer by focusing on the nature of cell-cell contacts in human oral cancer cells. The long-term goal of our studies is to determine the role of N-glycosylation in the formation of E-cadherin-mediated cell-cell contacts in oral cancer cells. E-cadherin, with its documented role as a tumor suppressor, is the principal cell-cell adhesion receptor in oral epithelial cells. Although changes in N-glycan structures have long been known to be corollaries of tumor formation and metastasis, no information is available about how these structures affect E-cadherin adhesive function. E-cadherin ectodomains, which function in the formation of homotypic cell-cell contacts, have several potential N-glycan addition sites, while the cytosolic tail binds catenins that provide the linkage to the actin cytoskeleton. We have shown that during cell proliferation and migration, E-cadherin is extensively N-glycosylated and present in unstable cell-cell contacts. In contrast, in cytodifferentiated cells, E-cadherin is scarcely N-glycosylated and found in stable junctional complexes associated with the actin cytoskeleton. Our initial studies in vivo and ex vivo show that inappropriate increase in E-cadherin N-glycosylation in differentiated salivary cells reverses E-cadherin-mediated cell-cell contacts from stable to weak. Importantly, many cancer cells have highly N-glycosylated E-cadherin that is present in weak cell-cell contacts. Our hypothesis is that the N-glycosylation status of E- cadherin regulates its tumor suppressive function. We propose to test this hypothesis in 4 specific aims: 1) to demonstrate that highly N-glycosylated E-cadherin is a characteristic of oral cancer cell lines; 2) to show that high levels of E-cadherin N-glycosylation drive the formation of unstable E-cadherin-mediated cell-cell contacts; 3) to determine the signaling events through which N-glycosylation status of E-cadherin affects oral cancer cell proliferation and survival; and 4) to show that N-glycosylation status of E-cadherin regulates its tumor suppressive activity in SCID mice in vivo. Our proposed studies will increase the understanding of the basis of E-cadherin tumor suppressive activity in oral cancer and will serve as a basis for the development of novel treatment strategies.