Role of the polypeptide N-acetylgalactosaminyltransferase 3 in ovarian cancer progression: possible implications in abnormal mucin O-glycosylation

Abstract

Previously, we have identified the polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3) gene as notably hypomethylated in low-malignant potential (LMP) and high-grade (HG) serous epithelial ovarian tumors, compared to normal ovarian tissues. Here we show that GALNT3 is strongly overexpressed in HG serous EOC tumors as compared to normal ovarian tissue. Moreover, the GALNT3 expression significantly correlated with shorter progression-free survival (PFS) intervals in epithelial ovarian cancer (EOC) patients with advanced disease.Knockdown of the GALNT3 expression in EOC cells led to sharp decrease of cell proliferation and induced S-phase cell cycle arrest. Additionally, GALNT3 suppression significantly inhibited EOC cell migration and invasion. Gene expression profiling and consecutive network and pathway analyses confirmed these findings, as numerous genes and pathways known previously to be implicated in ovarian tumorigenesis, including EOC tumor invasion and metastasis, were found to be downregulated upon GALNT3 suppression, while some tumor suppressor genes were induced. Moreover, GALNT3 downregulation was associated with reduced MUC1 protein expression in EOC cells, probably related to destabilization of the MUC1 protein due to lack of GALNT3 glycosylation activity. GALNT3 knockdown was also accompanied with increase of the cell adhesion molecules β-catenin and E-cadherin, which are normally suppressed by MUC1 in cancer, thus supporting the role of the GALNT3-MUC1 axis in EOC invasion.Taken together, our data are indicative for a strong oncogenic potential of the GALNT3 gene in advanced EOC and identify this transferase as a novel EOC biomarker and putative EOC therapeutic target. Our findings also suggest that GALNT3 overexpression might contribute to EOC progression through aberrant mucin O-glycosylation

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

“…In this study, we found that overexpression of C1GALT1 decreases Tn antigens and increases T antigens on cell surfaces and MUC1 and enhances breast cancer cell malignant behaviors. However, previous studies show that increased Tn and sTn antigens correlate with poor prognosis in various cancers [9, 34]. The explanation for this discrepancy may be that malignant phenotypes are regulated by many factors and not all of them can increase Tn expression.…”

Influenza A Virus-Induced Expression of a GalNAc Transferase, GALNT3, via MicroRNAs Is Required for Enhanced Viral Replication

“…Although galnt3-KO mice exhibit testicular calcifications and male infertility (30), it is unlikely that FGF23 is directly involved in the replication of IAV due to the fact that the expression of FGF23 has not been demonstrated in respiratory epithelial cells. However, a recent study revealed that GALNT3 suppression results in the up-or downregulation of numerous genes associated with the pathways involved in transcriptional regulation, signal transduction, cell proliferation, immune and inflammatory responses, and mucin O-glycosylation modification in epithelial ovarian cancer cells, demonstrating that GALNT3 contributes to various cellular processes through the O-glycosylation of many unknown substrates (55). In this respect, it is conceivable that GALNT3 affects IAV replication by modifying the O-linked glycosylation of unknown cellular factor(s) that may be involved in the activity of viral polymerase.…”

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

“…GALNT2 down-regulation contributes to HCC cell malignant behaviors and enhances gastric cell proliferation and invasion [11, 12]. GALNT3 is frequently up-regulated in renal cell carcinoma (RCC) and independently predicts high-grade tumor and poor survival [13]; similarly GALNT3 is also up-regulated in high-grade serous epithelial ovarian cancer (EOC) and is correlated with shorter progression-free survival in advanced stage EOC [14]. Up-regulation of GALNT14 was correlated with ovarian carcinogenesis [15].…”