Fucosyltransferase 8 as a functional regulator of nonsmall cell lung cancer

Abstract

The up-regulation of fucosyltransferase 8 (FUT8), the only enzyme catalyzing α1,6-fucosylation in mammals, has been observed in several malignant cancers including liver, ovarian, thyroid, and colorectal cancers. However, the pathological role and the regulatory mechanism of FUT8 in cancers remain largely unknown. In the current study, we report that the expression of FUT8 is up-regulated in nonsmall cell lung cancer (NSCLC) and correlates with tumor metastasis, disease recurrence, and poor survival in patients with NSCLC. Knocking down FUT8 in aggressive lung cancer cell lines significantly inhibits their malignant behaviors including in vitro invasion and cell proliferation, as well as in vivo metastasis and tumor growth. The results of glycoproteomic and microarray analyses show that FUT8 globally modifies surface antigens, receptors, and adhesion molecules and is involved in the regulation of dozens of genes associated with malignancy, suggesting that FUT8 contributes to tumor progression through multiple mechanisms. Moreover, we show that FUT8 is up-regulated during epithelial-mesenchymal transition (EMT), a critical process for malignant transformation of tumor, via the transactivation of β-catenin/lymphoid enhancer-binding factor-1 (LEF-1). These results provide a model to illustrate the relation between FUT8 expression and lung cancer progression and point to a promising direction for the prognosis and therapy of lung cancer.TGF-beta | E-cadherin | fucose F ucosylation, the transfer of fucose from GDP-fucose to glycoconjugates such as glycoproteins and glycolipids, is catalyzed by a family of enzymes called fucosyltransferases (FUTs). So far, 13 FUTs are known to be encoded by the human genome, including FUT1 to 11, protein O-fucosyltransferase 1 (POFUT1), and POFUT2. Through these FUTs, fucoses could be attached to N-, O-, and lipid-linked glycans through an α1,2-(by FUT1 and 2), α1,3-(by FUT3 to 7 and FUT9 to 11), α1,4-(by FUT3 and 5), or α1,6-(by FUT8) linkage, or directly link to the serine/threonine residues of EGF-like or thrombospondin repeats (by POFUT1 and 2, respectively) (1, 2). In mammals, fucosylated glycans have pivotal roles in many aspects of biological processes such as lymphocyte homing, immune responses, fertilization, and development (3). Moreover, aberrant fucosylation, which results from the deficiency or overexpression of FUTs, is associated with a variety of human diseases, including cystic fibrosis, leukocyte adhesion deficiency type II, and cancers (3, 4).Unlike other FUTs, which are functionally redundant, FUT8 is the only enzyme responsible for the α1,6-linked (core) fucosylation by adding fucose to the innermost GlcNAc residue of an N-linked glycan. A growing body of evidence indicates that core fucosylation is important for regulating protein functions. For example, deletion of the core fucose from the Fc region of IgG1 greatly improves its binding affinity to Fcγ receptor IIIa, which in turn enhances antibody-dependent cell-mediated cytotoxicity for over 50 folds (5, 6). Co...

Expression of Fucosyltransferase 8 Is Associated with an Unfavorable Clinical Outcome in Non-Small Cell Lung Cancers

“…Consistent with our present observation, they also reported that expression of FUT8 correlated with poor survival in patients with NSCLCs. However, their analyses included cases with noncurative and curative resection, and 45 of 140 cases (32%) were classified as stage IV with metastasis [28]. In the present study, we have clarified for the first time that expression of FUT8 correlates with a short survival period and poor prognosis in patients with curatively resected and pStage I NSCLCs.…”

“…Loss of core fucose on epidermal growth factor receptor and transforming growth factor β 1 receptor reduces the ligand binding ability as well as downstream signaling [26,27]. Recently, Chen et al [28] have reported that expression of FUT8 is involved in the malignant behaviors of lung cancer cell lines, including in vitro invasion and cell proliferation, as well as in vivo metastasis and tumor growth. Using glycoproteomic and microarray analyses, they have shown that FUT8 globally modifies cell surface antigens, receptors, and adhesion molecules and that it is involved in the regulation of many genes associated with malignancy, suggesting that FUT8 contributes to tumor progression through multiple mechanisms.…”

Glycobiology Modifications in Intratumoral Hypoxia: The Breathless Side of Glycans Interaction

“…Changes in the N-glycosylation process can be related to oncogenesis and cancer progression. In fact, these structural changes are important in understanding the implications of the adhesive properties of cancer cells [105, 106]. …”

Development of orally active inhibitors of protein and cellular fucosylation

“…Several clinical trials of fucose-deficient mAbs are under way (22)(23)(24)(25)(26)(27), and mogamulizumab, an anti-CC chemokine receptor 4 mAb lacking core fucosylation has received marketing approval in Japan for the treatment of relapsed or refractory adult T-cell leukemia/ lymphoma (28). Other fucosylated glycans of interest include sialyl Lewis X (sLeX), sialyl Lewis A, and Lewis Y (LeY), which are on cell surfaces and have been associated with malignancy, tumor progression, and inflammation (6,21,29,30).…”