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GALNT3 is a novel target driving lymphomagenesis via O-glycosylation of FGFR2

ABSTRACT: Despite the dual roles of GALNT3 in various cellular processes related to tumorigenesis and solid tumors, the clinical and biological significance of GALNT3 in lymphomagenesis remains largely unknown. Herein, our bioinformatics analysis uncovers that GALNT3 dependent glucose metabolism was significantly elevated in DLBCL. Our DLBCL cohort study revealed that GALNT3 positivity is significantly associated with worse prognosis and clinical outcomes in DLBCL pathogenesis. Biologically, GALNT3 overexpression were found to promote DLBCL cell proliferation and cell cycle progression, while silencing GALNT3 inhibited lymphomagenesis. RNA-seq uncovers that GALNT3 upregulated FGFR2-MAPK signaling pathway in DLBCL. Moreover, protein mass spectrometry identified two potential O-glycosylation sites of FGFR2 (Thr319 and Ser299). Further point mutation of glycosylation sites, conﬁrmed that GALNT3 O-glycosylates FGFR2 through Thr319. Besides, in vitro and in vivo rescue experiments demonstrated that Thr319 is dispensable for GALNT3-FGFR2-MAPK induced lymphomagenesis. In vitro pharmacological inhibition of FGFR2 with a selective inhibitor Futibatinib further demonstrated that Futibatinib inhibits DLBCL cell growth, cell proliferation, induced cell cycle arrest, promoted cell apoptosis. Further in vivo study also indicated that combination of Futibatinib with chemotherapy demonstrated better anti-tumor activity relative to single drug therapy in DLBCL treatment. Collectively, our data highlight the importance of considering the GALNT3-FGFR2-MAPK signaling axis as an attractive therapeutic target for lymphomagenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE285695 | GEO | 2026/01/28

REPOSITORIES: GEO

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Project description: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 both LMP and HG serous EOC tumors, thus suggesting that epigenetic mechanisms might be implicated in GALNT3 overexpression in serous epithelial ovarian cancer (EOC). Moreover, GALNT3 expression significantly correlated with shorter progression-free survival (PFS) periods in serous 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.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 ovarian etiology through aberrant mucin O-glycosylation. To better understand the molecular mechanisms of GALNT3 gene action in ovarian cancer cells, we employed the Agilent Whole Human Genome microarrays, containing ~ 44,000 genes to identify global gene expression changes upon GALNT3 suppression in A2780s cells. We compared the gene expression of the previously selected clone shRNA- GALNT3-knockdown clones 1 & 2 (sh-cl1 & sh-cl2) against the corresponding control (ctrl) clone. The microarray experiments were performed in duplicates, as four hybridizations were carried out for the GALNT3-suppressing cell clones against the corresponding control, using a fluorescent dye reversal (dye-swap) technique.

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GALNT3 is a novel target driving lymphomagenesis via O-glycosylation of FGFR2

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