FUT8 Alpha-(1,6)-Fucosyltransferase in Cancer

Abstract

Aberrant glycosylation is a universal feature of cancer cells that can impact all steps in tumour progression from malignant transformation to metastasis and immune evasion. One key change in tumour glycosylation is altered core fucosylation. Core fucosylation is driven by fucosyltransferase 8 (FUT8), which catalyses the addition of α1,6-fucose to the innermost GlcNAc residue of N-glycans. FUT8 is frequently upregulated in cancer, and plays a critical role in immune evasion, antibody-dependent cellular cytotoxicity (ADCC), and the regulation of TGF-β, EGF, α3β1 integrin and E-Cadherin. Here, we summarise the role of FUT8 in various cancers (including lung, liver, colorectal, ovarian, prostate, breast, melanoma, thyroid, and pancreatic), discuss the potential mechanisms involved, and outline opportunities to exploit FUT8 as a critical factor in cancer therapeutics in the future.

Keywords: cancer; fucosylation; fut8; glycosylation.

Figure 1

The reaction catalysed by FUT8. FUT8 transfers an l-fucose reside from GDP-β-l-fucose (GDP-Fuc) onto the innermost GlcNAc of an N-glycan to form an α-1,6 linkage.

Figure 2

The sythetic pathway for GDP-fucose. GDP-fucose, an essential component of core fucosyaltion is produced by two different pathways within the cell. The predominat de novo pathway relies on GMD and FX proteins. Adapted from [32].

Figure 3

Structure of FUT8. Published by [43] and reproduced with permission. (a) Ribbon structure of HsFUT8 with orange carbon atoms representing GDP and green carbon atoms representing a bi-antennary complex N-glycan (G0). The coiled-coil domain is colored in gray, the catalytic domain in red, and the SH3 domain in orange. The interdomain α3 and loop β10–β11 are colored in blue and aquamarine, respectively. Yellow sulfur atoms indicate disulfide bridges. The C-terminal loop is colored in black. Electron density maps are F_O–F_C (blue) contoured at 2.2σ for GDP and G0. (b) Surface representation of the HsFUT8-GDP-G0 complex.