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.