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

Abstract

Edited by Gerald W. HartDeregulated expression of N-acetylgalactosaminyltransferases (GALNTs), which is responsible for the initial step of mucin-type O-glycosylation, could produce abnormal truncated O-glycans and thereby exert pivotal functions during malignant transformation. GALNT4 is one of the few isoforms preferring to catalyze partial GalNAc-glycosylated substrates and modify the sites not utilized by other known GALNTs. This study aims to evaluate the impact of GALNT4 expression on malignant transformation of hepatocellular carcinoma (HCC). Immunohistochemistry and in situ hybridization analysis were performed to assess GALNT4 and miR-9 level in clinical specimens, respectively. GALNT4 expression is markedly repressed in primary HCC tissues, and reduced expression of GALNT4 is significantly associated with adverse survival of patients with HCC. Functional investigations demonstrate that repressed GALNT4 could promote migration, invasion, anoikis resistance, and stemness of HCC cells in vitro as well as tumor growth in vivo. The wild-type GALNT4 could modify O-linked glycosylation on EGFR and thus modulate the activity of EGFR. A luciferase activity assay further identified microRNA-9 (miR-9) as the crucial specific arbitrator for GALNT4 expression in HCC cells. Furthermore, restoring GALNT4 expression attenuates miR-9-mediated oncogenic functions. Kaplan-Meier survival analysis indicates that the miR-9/GALNT4 expression signature yields promising prognostic significance to refine the risk stratification of patients with HCC. In conclusion, this study establishes the miR-9/ GALNT4 axis as a potential adverse prognostic factor and therapeutic target for HCC patients.

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

“…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. Furthermore, these changes have not been correlated with Tn levels, and it is unlikely that increased GALNT expression alone could drive Tn levels (Ju et al, 2013).…”

Hepatitis C Virus-Induced FUT8 Causes 5-FU Drug Resistance in Human Hepatoma Huh7.5.1 Cells

“…FUT8 transfers the fucose moiety from guanosine diphosphate-β-L-fucose to the innermost GlcNAc residue in N-glycans, denoted as core fucose [22]. Extensive literature indicates that alteration of glycosylation occurs during the progression of HCC [23,24]. Thus, FUT8 might have an important role in the development of HCC or in HCV infection.…”

The Role of Noncoding RNAs in the Regulation of Anoikis and Anchorage-Independent Growth in Cancer

“…In hepatocellular carcinoma, miR-9-5p levels are elevated, and this miRNA enhances the stemness and anoikis resistance of cancer cells by targeting polypeptide N-acetylgalactosaminyltransferase 4 (GALNT4) ( Figure 1 and Table 1 ). Further investigations showed that GALNT4 attenuates the stemness and anchorage-independent survival of hepatocellular carcinoma cells in vitro and inhibits cancer cell growth in vivo partly via inactivating epidermal growth factor receptor (EGFR) [ 29 ].…”