Knockdown of GALNT1 suppresses malignant phenotype of hepatocellular carcinoma by suppressing EGFR signaling

Abstract

O-glycosylation is a common protein modification. Aberrant O-glycosylation is associated with many cancers. GALNT1 is a GalNAc-transferase that initiates protein O-glycosylation. We found that GALNT1 is frequently up-regulated in hepatocellular carcinoma (HCC) and is associated with poor patient survival. Overexpression of GALNT1 increased and knockdown decreased HCC cell migration and invasion. Knockdown of GALNT1 inhibited EGF-induced migration and invasion. Knockdown of GALNT1 decreased EGFR activation and increased EGFR degradation, by decreasing EGFR O-glycosylation. This study demonstrates that down-regulation of GALNT1 is sufficient to suppress malignant phenotype of HCC cells by decreasing EGFR signaling. Thus, GALNT1 is a potential target in HCC.

Organelle Specific O-Glycosylation Drives MMP14 Activation, Tumor Growth, and Metastasis

“…For instance, an increased expression of GALNT3 (Taniuchi et al, 2011) and -T6 (Li et al, 2011) is found in pancreatic cancers, whereas elevated -T6 and -T14 expression is linked with breast cancer (Park et al, 2010;Wu et al, 2010). In hepatocellular carcinoma (HCC), GALNT1 levels are upregulated, and its depletion in a model of HCC causes a marked reduction in tumor formation (Huang et al, 2015). Yet others have shown that GALNT2 and -T4 are decreased in HCC (Liu et al, 2017;Wu et al, 2011), and it remains unclear whether these increases in expression are sufficient to exert a significant biological effect.…”

Down-regulation of Krüppel-like factor-4 by microRNA-135a-5p promotes proliferation and metastasis in hepatocellular carcinoma by transforming growth factor-β1

“…Recent studies have demonstrated that hepatocarcinogenesis linked with two main pathogenic mechanisms: (1) cirrhosis associated with hepatitis infection (for example, HBV or HCV), toxins (for example, alcohol or aflatoxin) or metabolic influences, and (2) mutations of oncogenes or tumor suppressor genes [2]. The mechanisms are involved in several important cellular signaling pathways, including EGF/EGFR [3], PI3K/AKT/mTOR [4, 5], RAF/MEK/ERK [6], HGF/c-MET [7] and WNT/β-catenin [8]. Besides that, clinical researches suggest that molecularly targeted drugs block critical signaling pathways to treat for advanced HCC.…”

Loss of N-Acetylgalactosaminyltransferase-4 Orchestrates Oncogenic MicroRNA-9 in Hepatocellular Carcinoma

“…Because previous studies have well documented that GALNT1, GALNT2, and GALNT10 can modify the O-glycosylation of epidermal growth factor receptor (EGFR) in HCC cells (13,14,17), we next aimed at distinguishing GALNT4 from these GALNTs or establishing similarities for the activity of EGFR in HCC cells. Our data showed that the membrane EGFR level was not affected by GALNT4 (Fig.…”

“…Previous studies have revealed that both GALNT1 and GALNT2 play pivotal roles in HCC tissues and cells (13,14). Both of them could modify O-glycosylation of EGFR but exert opposite effects on the activity and stabilization of EGFR, which indicates that different ppGalNAc T isoforms, including GALNT4, might have different specific substrates and/or prefer modifying sites.…”

“…GALNT14 might modulate apoptoticsignalingofcancercellsthroughmodifyingtheproapoptotic receptors (12). The vital roles of GALNT1 and GALNT2 in HCC have been well elaborated (13,14). GALNT4 is one of the isoforms preferring to catalyze partial GalNAc-glycosylated substrates and modify the sites not utilized by other known GALNTs (15,16).…”