Initiation of GalNAc-type O-glycosylation in the endoplasmic reticulum promotes cancer cell invasiveness

Abstract

Invasiveness underlies cancer aggressiveness and is a hallmark of malignancy. Most malignant tumors have elevated levels of Tn, an O-GalNAc glycan. Mechanisms underlying Tn up-regulation and its effects remain unclear. Here we show that Golgi-to-endoplasmic reticulum relocation of polypeptide N-acetylgalactosamine-transferases (GalNAc-Ts) drives high Tn levels in cancer cell lines and in 70% of malignant breast tumors. This process stimulates cell adhesion to the extracellular matrix, as well as migration and invasiveness. The GalNAc-Ts lectin domain, mediating high-density glycosylation, is critical for these effects. Interfering with the lectin domain function inhibited carcinoma cell migration in vitro and metastatic potential in mice. We also show that stimulation of cell migration is dependent on Tn-bearing proteins present in lamellipodia of migrating cells. Our findings suggest that relocation of GalNAc-Ts to the endoplasmic reticulum frequently occurs upon cancerous transformation to enhance tumor cell migration and invasiveness through modification of cell surface proteins.

Mammalian O-mannosylation of cadherins and plexins is independent of protein O-mannosyltransferases 1 and 2

“…In vitro studies with peptides have further supported this (24), and here we provided evidence that elimination of POMT-driven O-mannosylation of ␣-DG in HEK293 cells results in GalNAc glycosylation at sites normally occupied by O-Man glycans, as shown previously by in vivo studies in Drosophila melanogaster (50). In normal human cells, the two glycosylation processes are topologically separated in ER and Golgi, but in cancer the GalNAc-Ts may relocate to the ER and thus potentially compete with POMTs (51,52). In this study we did not consider the POMGnT2 pathway (Fig.…”

Probing the O-Glycoproteome of Gastric Cancer Cell Lines for Biomarker Discovery*

“…A third potential mechanism offered recently may be related to cancer-associated relocation of the polypeptide GalNAc-transferases (GalNAc-Ts) that initiate O-glycosylation ( Fig. 1) from Golgi to ER, which appear to induce expression of the Tn truncated O-glycans, although expression of STn has not been explored yet (27).…”

Sugars and cell adhesion: The role of ST6GalNAc1 in prostate cancer progression

“…Although the mechanism and biological significance of the truncated O-glycophenotype remains to be widely addressed, the expression of truncated O-glycans in cancer is thought to result from several different mechanisms, including altered expression, localisation or topology of glycosyltransferases [5][6][7][8] , and fluctuations in cellular pH [9,10] . O-glycosylation is an abundant protein modification; More than 80% of the human proteome that enters and passes through the secretory apparatus is predicted to be O-glycosylated [11] .…”