Suppression of FUT1 attenuates cell proliferation in the HER2-overexpressing cancer cell line NCI-N87

Lewis Y (LeY) antigen is an oligosaccharide that is highly expressed atthe cell surface in various human cancers. Increased LeY expression activatesepidermal growth factor receptor (EGFR) and human epidermal growth factor receptor2 (HER2) and promotes cell proliferation in EGFR-overexpressing cells. However,the effect of downregulation of LeY expression on cell proliferation in HER2-overexpressingcells remains unknown. FUT1 encodes α1,2-fucosyltransferase, a key enzyme forLeY synthesis. We knocked down FUT1 by short interfering RNA (siRNA) in four HER2-overexpressinghuman cancer cell lines, including NCI-N87, MKN7, SKBr3 and BT474. We investigatedwhether downregulation of LeY and alteration in the glycosylation status of thesecells affect cell proliferation and HER2 activation. Knocking down FUT1 expressionmarkedly inhibited proliferation of NCI-N87, which highly expressed EGFR and wassensitive to EGFR deprivation. Furthermore, FUT1 siRNA downregulated the totalamount of HER2 protein, phosphorylation of HER2 and EGFR, and phosphorylationof extracellular signal-regulated kinase (ERK) in this cell line. Moreover, themarked downregulation of phosphorylation of HER2 and ERK was observed followingshort-time EGF-stimulation. These effects were not observed in the other threecell lines. Our results suggest that knockdown of FUT1 downregulates HER2 signalingvia EGFR downregulation. FUT1 may serve as a new molecular target for HER2-overexpressinghuman cancers with activated EGFR signaling.