Fucosyltransferase 4 shapes oncogenic glycoproteome to drive metastasis of lung adenocarcinoma

Abstract

Aberrant fucosylation plays critical roles in lung cancer progression. Identification of the key fucosyltransferase as a therapeutic target may refine lung cancer management.Here, we identified a terminal α1,3-fucosyltransferase, FUT4, as the key prognostic predictor for lung adenocarcinoma through a transcriptomic screen in lung cancer cohorts. Overexpression of FUT4 promoted lung cancer invasion, migration, epithelialto-mesenchymal transition and cell adhesion in vitro, which can be reversed by genetic depletion of the enzyme. Notably, knockdown of FUT4 markedly curtailed lung colonization and distant metastases of lung adenocarcinoma cells in mouse xenograft models. Moreover, immunoprecipitation-mass spectrometry with anti-Lewis x, a major fucosylated glycan generated by FUT4, revealed increased fucosylation on cascade proteins of multiple oncogenic signalings including epidermal growth factor (EGF) and transforming growth factor-β (TGF-β) pathways with concomitant transcriptional activation. The malignant phenotype provoked by FUT4-mediated fucosylproteomic networks can be pharmacologically diminished as treating FUT4-high expressing cells with EGFR inhibitors showed reduced metastatic capacity in vivo. Collectively, FUT4 represents a promising therapeutic target in lung cancer metastasis. Our data highlight the potential for integration of glycomics into precision medicine-based therapeutics.

Analytical method validation and quantitation of 3-fucosyllactose in Korean maternal milk by mass spectrometry

“…The primary enzyme responsible for the synthesis of 3-FL is α-1,3-fucosyltransferase (FUT3), which is encoded by the Lewis gene fut3. Besides FUT3, other fucosyltransferases such as FUT 4-7 and 9-11, which are Se− and Le− independent, could catalyze the fucosylation with α-1,3-linkage (Lu, et al, 2019). As a result, 3-FL can be detected in the milk of both Se+/and Le+/-mothers (Tonon, et al, 2019).…”