C1GALT1 high expression is associated with poor survival of patients with pancreatic ductal adenocarcinoma and promotes cell invasiveness through integrin αv

Abstract

Pancreatic adenocarcinoma (PDAC) is a leading cause of cancer-related death. Altered glycosylation contributes to tumor progression and chemoresistance in many cancers. C1GALT1 is the key enzyme controlling the elongation of GalNAc-type O-glycosylation. Here we showed that C1GALT1 was overexpressed in 85% (107/126) of PDAC tumors compared with adjacent non-tumor tissues. High expression of C1GALT1 was associated with poor disease-free and overall survival (n = 99). C1GALT1 knockdown using siRNA suppressed cell viability, migration, and invasion as well as increased gemcitabine sensitivity in PDAC cells. In contrast, C1GALT1 overexpression enhanced cell migration and invasion. In subcutaneous and pancreatic orthotopic injection models, C1GALT1 knockdown decreased tumor growth and metastasis of PDAC cells in NOD/SCID mice. Mechanistically, C1GALT1 knockdown dramatically suppressed cell-extracellular matrix (ECM) adhesion, which was associated with decreased phosphorylation of FAK at Y397/Y925 and changes in O-glycans on integrins including the β1, αv, and α5 subunits. Using functional blocking antibodies, we identified integrin αv as a critical factor in C1GALT1-mediated invasiveness of PDAC cells. In conclusion, this study not only reveals that C1GALT1 could be a potential therapeutic target for PDAC but also provides novel insights into the role of O-glycosylation in the α subunits of integrins.

C1GALT1, Negatively Regulated by miR-181d-5p, Promotes Tumor Progression via Upregulating RAC1 in Lung Adenocarcinoma

“…In addition, overexpression or knockdown of C1GALT1 could facilitate or suppress tumor growth in vivo . It has been reported that C1GALT1 is essential for processes such as cell proliferation, migration, and invasion in a variety of malignancies ( Lee et al, 2020 ; Kuo et al, 2021 ). Our findings are consistent with previous reports, suggesting a pro-oncogenic role for C1GALT1 in LUAD.…”

“…Hence, RAC1 was a downstream effector of C1GALT1 in LUAD. Previous studies have mainly focused on the relationship between C1GALT1 and glycoproteins ( Lee et al, 2020 ; Kuo et al, 2021 ). Besides its direct function of producing aberrant glycoproteins, our current study provided new insights into the regulatory network of C1GALT1.…”

“…Core 1 β1, 3-galactosyltransferase 1 (C1GALT1), an exclusive T-synthase in mammalian cells, catalyzes the transfer of galactose (Gal) from UDP-Gal to the extant GalNAc forming core 1 O-glycans (Galβ1, 3GalNAcα-O-Ser/Thr) ( Liu et al, 2020 ). Studies have shown that C1GALT1 is abnormally expressed in a variety of malignant tumors, such as gastric cancer ( Lee et al, 2020 ), head and neck cancer ( Lin et al, 2018 ), pancreatic ductal adenocarcinoma ( Kuo et al, 2021 ), laryngeal carcinoma ( Dong et al, 2018b ), ovarian cancer ( Chou et al, 2017 ), and hepatocellular carcinoma ( Wu et al, 2013 ). However, the role of C1GALT1 in lung cancer remains unclear.…”

SLC4A2 anion exchanger promotes tumour cell malignancy via enhancing net acid efflux across golgi membranes

“…In addition, impaired O-glycosylation and in particular, the extension of the (sialyl)Tnantigen to (sialyl)-T-antigen of the TRAIL death receptor was found to alter receptor oligomerization state and to confer apoptosis resistance to the cells [54]. Overexpression of C1GALT1, a key enzyme controlling the elongation of the Tn-antigen to T-antigen in turn was also found to enhance migration, invasion, tumour growth, and metastasis of pancreatic cancer cells [58]. In line with these observations, our lectin microarray analyses showed that the levels of these truncated O-glycan glycotopes were much lower in non-invasive AE2 knockdown cells than in invasive (SW-48 Scr) cells.…”

Integrated Systems-Analysis of the Human and Murine Pancreatic Cancer Glycomes Reveal a Tumor Promoting Role for ST6GAL1

“…Heterologous expression of human enzymes that can biosynthesize CA-19-9 in a mouse model increased pancreatic inflammation, pointing to a potential role of this epitope in disease initiation (4). Pancreatic cell culture models have also shown a potential role for glycosylation in cell stemness, invasiveness and drug resistance (5)(6)(7)(8).…”