Protein N-glycosylation in oral cancer: Dysregulated cellular networks among DPAGT1, E-cadherin adhesion and canonical Wnt signaling

Abstract

N-Linked glycosylation (N-glycosylation) of proteins has long been associated with oncogenesis, but not until recently have the molecular mechanisms underlying this relationship begun to be unraveled. Here, we review studies describing how dysregulation of the N-glycosylation-regulating gene, DPAGT1, drives oral cancer. DPAGT1 encodes the first and rate-limiting enzyme in the assembly of the lipid-linked oligosaccharide precursor in the endoplasmic reticulum and thus mediates N-glycosylation of many cancer-related proteins. DPAGT1 controls N-glycosylation of E-cadherin, the major epithelial cell–cell adhesion receptor and a tumor suppressor, thereby affecting intercellular adhesion and cytoskeletal dynamics. DPAGT1 also regulates and is regulated by Wnt/β-catenin signaling, impacting the balance between proliferation and adhesion in homeostatic tissues. Thus, aberrant induction of DPAGT1 promotes a positive feedback network with Wnt/β-catenin that represses E-cadherin-based adhesion and drives tumorigenic phenotypes. Further, modification of receptor tyrosine kinases (RTKs) with N-glycans is known to control their surface presentation via the galectin lattice, and thus increased DPAGT1 expression likely contributes to abnormal activation of RTKs in oral cancer. Collectively, these studies suggest that dysregulation of the DPAGT1/Wnt/E-cadherin network underlies the etiology and pathogenesis of oral cancer.

FT-IR Spectroscopy Study in Early Diagnosis of Skin Cancer

“…The formed products are similar to those that were also produced upon irradiation of polysaccharides or by using cupric ions (Cu 2+ ) and ascorbic acid (27)(28)(29). The glycosylation has also been shown in other cancers, such as breast and metastatic bone cancers (12,22,30). Furthermore, HA and its CD44 cellular receptors, and the receptor for HA-mediated motility/intracellular HA-binding protein have also been linked to cancer progression and metastasis (31)(32)(33)(34).…”

Orthotopic non-metastatic and metastatic oral cancer mouse models

“…We have shown previously that human OSCC is characterized by deregulated E-cadherin adhesion and increased expression of the N-glycosylation regulating gene, DPAGT1 [20,26,27]. Compared to CAL27-induced tumors, the UMSCC2 tumors exhibited more prominent staining intensity for the DPAGT1 protein, GPT, in subsets of tumor cells.…”

Lefty Glycoproteins in Human Embryonic Stem Cells: Extracellular Delivery Route and Posttranslational Modification in Differentiation

“…Differential processing or glycosylation per se could provide fine-tuning of protein properties in a cell-or tissue-specific manner without any changes in the amino acid sequence of the protein. Support for such a premise is emerging from studies that depict differential glycosylation as a key regulator of inter-and specifically extracellular signaling [42][43][44], and in directing pluripotency and differentiation of pluripotent stem cells [45].…”