C1GALT1 overexpression promotes the invasive behavior of colon cancer cells through modifying O-glycosylation of FGFR2

Abstract

Core 1 β1,3-galactosyltransferase (C1GALT1) transfers galactose (Gal) to N-acetylgalactosamine (GalNAc) to form Galβ1,3GalNAc (T antigen). Aberrant O-glycans, such as T antigen, are commonly found in colorectal cancer. However, the role of C1GALT1 in colorectal cancer remains unclear. Here we showed that C1GALT1 was frequently overexpressed in colorectal tumors and is associated with poor survival. C1GALT1 overexpression promoted cell survival, migration, invasion, and sphere formation as well as tumor growth and metastasis of colon cancer cells. Conversely, knockdown of C1GALT1 with small interference (si) RNA was sufficient to suppress these malignant phenotypes in vitro and in vivo. Moreover, we are the first to show that fibroblast growth factor receptor (FGFR) 2 carried O-glycans in colon cancer cells. Mechanistic investigations showed that C1GALT1 modified the O-glycans on FGFR2 and enhanced bFGF-triggered activation of FGFR2 as well as increased bFGF-mediated malignant phenotypes. In addition, BGJ398, a selective inhibitor of FGFR, blocked the effects of C1GALT1. These findings suggest that C1GALT1 overexpression modifies O-glycans on FGFR2 and enhances its phosphorylation to promote the invasive behavior and cancer stem-like property in colon cancer cells, indicating a critical role of O-glycosylation in the pathogenesis of colorectal cancer.

GALNT14 promotes lung-specific breast cancer metastasis by modulating self-renewal and interaction with the lung microenvironment

“…Consistent with this possibility, a previous study reported that ALK3 and ActR-IIB are O-GalNAcylated by Xenopus Galntl-1 and that ActR-IIB glycosylation prevents its dimerization with BMPRI36. In addition, the O-GalNAcylation of FGFR2 by an unknown GALNT has been shown to trigger the activation of downstream signalling35. The biochemical mechanisms by which the GALNT14-stimulated O-GalNAcylation of FGFR1 activates the downstream cascade are currently under investigation.…”

“…The O-GalNAcylation of cell-surface receptors by GALNTs has been shown to regulate downstream signalling cascades203536. Since our data suggest that GALNT14 inhibits BMP signalling, we examined whether GALNT14 exerts this effect by the O-GalNAcylation of BMPRs.…”

Up-regulation of C1GALT1 promotes breast cancer cell growth through MUC1-C signaling pathway

“…Dysregulated expression of mucin-type O-glycans has evidently lead to aberrant cellular response, particularly in cancer cells [4, 31]. We recently reported that C1GALT1 is up-regulated in colorectal cancer [16] and hepatocellular carcinoma [15]. Up-regulation of C1GALT1 enhanced malignant phenotypes in colorectal cancer and hepatocellular carcinoma through FGFR2 and MET signaling pathways, respectively.…”

“…Knockout of C1GALT1 causes spontaneous colitis [12] and thrombocytopenia [13] in mice and modulates platelet cell surface glycoproteins involved in platelet synthesis and hematopoiesis [14]. We recently reported that C1GALT1 alters O-glycan structures on MET and enhances MET dimerization in hepatocellular carcinoma [15]; and C1GALT1 modifies O-glycans on FGFR2 and its downstream signaling involved in colorectal cancer malignant phenotypes [16]. Several studies reported that T antigens are overexpressed in breast cancer metastatic tumor cells and overexpression of T antigen regulates breast cancer malignant phenotypes [6, 17–19].…”

220: Up-regulation of C1GALT1 promotes breast cancer cell growth through MUC1-C signaling pathway

“…Knockout of C1GALT1 causes spontaneous colitis [12] and thrombocytopenia [13] in mice and modulates platelet cell surface glycoproteins involved in platelet synthesis and hematopoiesis [14]. We recently reported that C1GALT1 alters O-glycan structures on MET and enhances MET dimerization in hepatocellular carcinoma [15]; and C1GALT1 modifies O-glycans on FGFR2 and its downstream signaling involved in colorectal cancer malignant phenotypes [16]. Several studies reported that T antigens are overexpressed in breast cancer metastatic tumor cells and overexpression of T antigen regulates breast cancer malignant phenotypes [6,[17][18][19].…”