Role of fucosyltransferase IV in the migration and invasion of human melanoma cells

Abstract

Malignant melanoma is one of the most aggressive human tumor types, mainly due to its high invasion capability, metastatic properties, and the absence of effective treatments. Glycosylation serves a pivotal role in the migration and invasion of melanoma. However, differences in glycosylation between high and low metastatic melanoma cells and how these regulate migration and invasion by altering the expression of fucosyltransferases (FUTs) remain unclear. In the present study, matrix‐assisted laser desorption/ionization‐time‐of‐flight‐mass spectrometry (MALDI‐TOF‐MS) analysis revealed that the composition profiling of fucosylated N‐glycans differed between high metastatic C8161 and low metastatic A375P cells. Further analysis revealed that FUT4 expression was significantly increased in C8161 cells. Melanoma tissue arrays further demonstrated that FUT4 was overexpressed in metastatic samples. Altered FUT4 expression was accompanied by a change in the migration and invasion capacity of the cells. In addition, the migration and invasion potential of melanoma cells were decreased in C8161 and increased in A375P cells upon altering FUT4 expression levels by small interfering RNA or complementary DNA transfection. Furthermore, regulating FUT4 expression markedly modulated the activity of the phosphoinositide‐3‐kinase/Akt (PI3K/Akt) signaling pathway, which affected melanoma cell migration and invasion. In conclusion, FUT4 is a novel biomarker and regulator of the migration and invasion of melanoma cells and may serve as a therapeutic target for melanoma.

The Role of Glycosylation in Melanoma Progression

“…LTA (Lotus tetragonolobus agglutinin), the lectin that specifically recognizes fucose residue of glycans and L-fucose, reduced adhesion to fibronectin and collagen IV of all primary and metastatic cell lines and slightly decreased proliferation of metastatic but not primary melanoma cell lines [60]. A more recent report confirmed the importance of FUT4 in migration and invasion of human melanoma cells that occur through the activation of the PI3K/AKT signaling pathway [27] (Figure 1).…”

“…(5) ST3GAL1 promotes melanoma metastasis through AXL [20]; (6) GnT-III represses metastasis through regulation of EGFR, integrins and cadherins [24][25][26]; (7) FUT4 regulates melanoma cell migration and invasion through activation of the PI3K/AKT signaling pathway [27]; (8) GCNT3 promotes melanoma cell migration and invasion through stabilization of MCAM [28]. See text for details regarding the role of the reported glycosyltransferases.…”

“…Expression levels of FUT1/2, GCNT2 and GnT-III are high in early-stage and diminish during melanoma progression, whereas expression of FUT4/8, GCNT3, GnT-V, ST3GAL1, ST3GAL3 and ST6GAL1 are higher in late-stage melanomas. Glycosyltransferases may promote melanoma progression by several mechanisms: (1) interaction between Siglec1-expressing macrophages and metastatic cells facilitates metastatic colonization[21]; (2) loss of GCNT2 enhances growth factor receptor and integrin-mediated cell proliferation signaling pathways promoting melanoma growth and survival[22]; (3) Siglec-9/sialoligand interactions result in a tumor glycosylation-dependent circuit that suppresses CD8+ T cell effector responses in the tumor microenvironment[23]; (4) FUT8-mediated core fucosylation prevents L1CAM cleavage by plasmin, facilitating melanoma cell invasion[19];(5) ST3GAL1 promotes melanoma metastasis through AXL[20];(6) GnT-III represses metastasis through regulation of EGFR, integrins and cadherins[24][25][26]; (7) FUT4 regulates melanoma cell migration and invasion through activation of the PI3K/AKT signaling pathway[27]; (8) GCNT3 promotes melanoma cell migration and invasion through stabilization of MCAM[28]. See text for details regarding the role of the reported glycosyltransferases.…”

Overexpression of Fut 2, 4, and 8, and nuclear localization of Fut 4 in ovarian cancer cell lines induced by ascitic fluids from epithelial ovarian cancer patients

“…The remodeling of the cytoskeleton in SKOV‐3 cells, generated by contact with the five AFs, was reflected in the formation of cellular extensions such as lamellipodia, invadopodia, and filopodia, as previously reported within our work team (Toledo‐Leyva et al, 2018). These structures are highly fucosylated by Fut's enzymes (Escrevente et al, 2006), and associated with adhesion processes during metastasis acting as ligands for P and E selectins (Shan et al, 2020; Shirure et al, 2015) and integrins (Escrevente et al, 2006; Villegas‐Pineda et al, 2015, 2017). Previous reports from our laboratory demonstrated that AF also induces an overexpression of integrins α5, α6, and β3 in SKOV‐3 cells (Villegas‐Pineda et al, 2017), which suggests that there could be an interaction between the aforementioned receptors and the extensive extensions of fucosylated membranes as a consequence of the overexpression of Fut's, a hypothesis that would need experimental confirmation.…”

Non-cytotoxic carbon nanotubes bioconjugated with fucosyltransferase 4-derived peptides modulate macrophage polarization in vitro

“…Fucosyltransferase-4 (FUT4) is an enzyme indispensable for the type II Lewis's antigens synthesis, and its overexpression has been reported in leukemias and colon, breast, pancreas, lung, and gastric cancers [8][9][10][11][12][13]. Furthermore, FUT4 has been related to epithelium-mesenchymal transition, proliferation, and metastases during cancer development [11,14,15]. Thus, FUT4 is proposed as a possible therapeutic target to explore its use as an antigen in generating immunotherapies against ovarian cancer.…”