RT Journal Article
SR Electronic
T1 Fucosyltransferase 4 shapes oncogenic glycoproteome to drive metastasis of lung adenocarcinoma
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 752519
DO 10.1101/752519
A1 Hsuan-Hsuan Lu
A1 Shu-Yung Lin
A1 Rueyhung Roc Weng
A1 Yi-Hsiu Juan
A1 Yen-Wei Chen
A1 Hsin-Han Hou
A1 Zheng-Ci Hung
A1 Giovanni Audrey Oswita
A1 Yi-Jhen Huang
A1 Jin-Yuan Shih
A1 Chong-Jen Yu
A1 Hsing-Chen Tsai
YR 2019
UL http://biorxiv.org/content/early/2019/09/02/752519.abstract
AB 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, epithelial-to-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.Fucosyltransferase 4 is a major prognostic indicator in lung adenocarcinoma and drives lung cancer metastasis via fucosylation-mediated intensification of oncogenic signalingWe identified a terminal α1,3-fucosyltransferase, FUT4, as a key prognostic predictor for lung adenocarcinoma patients. Mechanistically, FUT4 mediates the metastatic phenotype via aberrant fucosylation of signaling cascade proteins and augments specific oncogenic signaling through epidermal growth factor (EGF) and transforming growth factor-β (TGF-β) pathways. As a result, FUT4 provokes cancer metastasis through promoting cell invasion, migration, epithelial-to-mesenchymal transition, and binding of selectins. Therapeutically, FUT4 high-expressing cells demonstrated enhanced sensitivity to the targeted therapy. Depletion of FUT4 or treatment with EGFR inhibitors mitigates lung cancer metastasis. Thus, FUT4 represents an oncogenic signaling amplifier and a potential therapeutic target in lung cancer metastasis.