Fucosyltransferase 4 shapes oncogenic glycoproteome to drive metastasis of lung adenocarcinoma

Abstract

Background Aberrant fucosylation plays a critical role in lung cancer progression. Nevertheless, the key fucosyltransferase with prognostic significance in lung cancer patients, the enzyme's intracellular targets, and complex molecular mechanisms underlying lung cancer metastasis remain incompletely understood. Methods We performed a large-scale transcriptome-clinical correlation to identify major fucosyltransferases with significant prognostic values. Invasion, migration, cell adhesion assays were performed using lung cancer cells subject to genetic manipulation of FUT4 levels. Genome-wide RNA-seq and immunoprecipitation-mass spectrometry were used to characterize major cellular processes driven by FUT4, as well as profiling its intracellular protein targets. We also performed lung homing and metastasis assays in mouse xenograft models to determine in vivo phenotypes of high FUT4-expressing cancer cells. Findings We show that FUT4 is associated with poor overall survival in lung adenocarcinoma patients. High FUT4 expression promotes lung cancer invasion, migration, epithelial-to-mesenchymal transition, and cell adhesion. FUT4-mediated aberrant fucosylation markedly activates multiple cellular processes, including membrane trafficking, cell cycle, and major oncogenic signaling pathways. The effects are independent of receptor tyrosine kinase mutations. Notably, genetic depletion of FUT4 or targeting FUT4-driven pathways diminishes lung colonization and distant metastases of lung cancer cells in mouse xenograft models. Interpretation We propose that FUT4 can be a prognostic predictor and therapeutic target in lung cancer metastasis. Our data provide a scientific basis for a potential therapeutic strategy using targeted therapy in a subset of patients with high FUT4-expressing tumors with no targetable mutations.

Autophagic tumor-associated macrophages promote the endothelial mesenchymal transition in lung adenocarcinomas through the FUT4/p-ezrin pathway

“…FUT4 is a key enzyme in the oligosaccharide synthesis of LEY (32). Recent studies have reported that FUT4 drives the metastasis of lung adenocarcinomas (33), and FUT4 overexpression is accompanied by EMT in breast cancer cells (34). In the current study, autophagic TAMs increased FUT4 expression.…”

Specific (sialyl-)Lewis core 2 O-glycans differentiate colorectal cancer from healthy colon epithelium

“…Moreover, the addition of another LacNAc creates a sialyl-dimeric Le X/A antigen O -glycan which is also specifically found in cancer ( Figure 1 F ). The fucosyltransferase FUT4 involved in the biosynthesis of sLe X antigen is overexpressed in colon cancer ( Figure S16 ) and it was previously associated with lung adenocarcinoma metastasis and poor patient prognosis 50 , 51 . It was also previously described that the upregulation of sLe X/A antigens in CRC is due to downregulation of B4GALNT2.…”

Nomograms Based on Serum N-glycome for Diagnosis of Papillary Thyroid Microcarcinoma and Prediction of Lymph Node Metastasis

“…FUT3 is involved in tumorigenesis, proliferation, and migration of pancreatic cancer [ 41 ]. FUT4 is correlated with higher metastatic potentials in lung cancer [ 42 ]. FUT6 is associated with metastatic colorectal cancer [ 43 ].…”