C1GALT1 Enhances Proliferation of Hepatocellular Carcinoma Cells via Modulating MET Glycosylation and Dimerization

Abstract

Altered glycosylation is a hallmark of cancer. The core 1 b1,3-galactosyltransferase (C1GALT1) controls the formation of mucin-type O-glycans, far overlooked and underestimated in cancer. Here, we report that C1GALT1 mRNA and protein are frequently overexpressed in hepatocellular carcinoma tumors compared with nontumor liver tissues, where it correlates with advanced tumor stage, metastasis, and poor survival. Enforced expression of C1GALT1 was sufficient to enhance cell proliferation, whereas RNA interferencemediated silencing of C1GALT1 was sufficient to suppress cell proliferation in vitro and in vivo. Notably, C1GALT1 attenuation also suppressed hepatocyte growth factor (HGF)-mediated phosphorylation of the MET kinase in hepatocellular carcinoma cells, whereas enforced expression of C1GALT1 enhanced MET phosphorylation. MET blockade with PHA665752 inhibited C1GALT1-enhanced cell viability. In support of these results, we found that the expression level of phospho-MET and C1GALT1 were associated in primary hepatocellular carcinoma tissues. Mechanistic investigations showed that MET was decorated with O-glycans, as revealed by binding to Vicia villosa agglutinin and peanut agglutinin. Moreover, C1GALT1 modified the O-glycosylation of MET, enhancing its HGF-induced dimerization and activation. Together, our results indicate that C1GALT1 overexpression in hepatocellular carcinoma activates HGF signaling via modulation of MET O-glycosylation and dimerization, providing new insights into how O-glycosylation drives hepatocellular carcinoma pathogenesis. Cancer Res; 73(17); 5580-90. Ó2013 AACR.

C1GALT1 Seems to Promote In Vitro Disease Progression in Ovarian Cancer

“…C1GALT1 has been shown to regulate angiogenesis, thrombopoiesis, and kidney development. 17,18 Moreover, we recently reported that C1GALT1 alters O-glycans on hepatocyte growth factor receptor, also known as MET, and enhances MET dimerization in hepatocellular carcinoma 19 ; modifies O-glycans on fibroblast growth factor receptor 2 and its downstream signaling involved in colorectal cancer malignant phenotypes 20 ; and enhances breast cancer malignant progression by modulating O-glycans on Mucin (MUC) 1 and promoting MUC1-C/Acatenin signaling pathway. 21 Although C1GALT1 and mucintype O-glycosylation have been shown to play crucial roles in a variety of biologic functions, the roles of C1GALT1 in ovarian cancer remain unclear.…”

Decreased Expression of Hepatocyte Nuclear Factor 4α (Hnf4α)/MicroRNA-122 (miR-122) Axis in Hepatitis B Virus-associated Hepatocellular Carcinoma Enhances Potential Oncogenic GALNT10 Protein Activity

“…The alteration of O-glycans attached to the epidermal growth factor receptor (EGFR) mediated by the down-regulation of GALNT2 plays a critical role in the malignant phenotype of HCC cells (22). Moreover, overexpression of core 1␤-1,3-galactosyltransferase activates hepatocyte growth factor signaling in hepatocellular carcinoma (23). Therefore, understanding the roles of O-glycosylation in hepatocellular carcinoma may provide novel insights into the pathogenesis of hepatocellular carcinoma.…”

Tumor-Associated Glycans and Their Functional Roles in the Multistep Process of Human Cancer Progression

“…N-glycans and related genes including MGAT5 are also known to affect growth factor receptor signaling (Matsumoto et al 2008 ;Park et al 2012 ; also reviewed in Lau and Dennis 2008 ). The glycan-related genes involved in O-glycan synthesis such as GALNT14 , GALNT2 , and C1GALT1 on death receptors, and growth factor receptors such as c-Met and EGFR have recently been suggested to affect cancer cell apoptosis and proliferation ( Wagner et al 2007 ;Wu et al 2011Wu et al , 2013. Altered expression of these glycans may well play significant roles during the course of carcinogenesis.…”