FUT1-triggered signalling pathway underlies HCC drug resistance and tumour recurrence

Results of a recent immunology study by researchers from the University of Hong Kong (HKU) have revealed fucosyltransferase 1 (FUT1) as the key component in protein kinase RNA-like endoplasmic reticulum kinase (PERK)–mediated signalling pathway underlying cancer stemness in hepatocellular carcinoma (HCC), and in driving drug resistance and tumour recurrence.

“Our study’s findings highlight the therapeutic potential of targeting FUT1 in nutrient-deprived HCC and other advanced tumours. Our results lay the foundation for designing a new α-[1,2]-fucoslyation inhibitor that sensitizes liver tumours to sorafenib, a first-line treatment for advanced HCC, and eradicates tumour-initiating cell [TIC] subsets,” said Dr Stephanie Ma of the School of Biomedical Science, HKU. [J Clin Invest 2021;131:e143377]

“Furthermore, overexpression of FUT1 and/or CD147, intercellular adhesion molecule 1 [ICAM-1], epidermal growth factor receptor [EGFR], and ephrin type A receptor 2 [EPHA2] fucosylation may serve as good prognostic markers for HCC patients,” added Ma.

Fucosylation, one of the most important types of glycosylation that impacts key processes supporting tumour progression and metastasis, consists of transfer of a fucose residue to oligosaccharides and protein, with the process regulated by fucosylatransferase (FUTs).

Results of previous studies demonstrated an association between aberrant expression of FUT and various cancers, such as HCC. HCC is characterized by rapid tumour growth, with the core of the tumour bulk being poorly vascularized. However, due to survival pressure, advanced HCC cells undergo molecular adaption that promotes clonal selection of highly malignant TIC phenotype, with enhanced survival in nutrient-deprived conditions, particularly in the innermost tumour regions.

In response to glucose deprivation, HCC cells activate cellular stress response of PERK-mediated unfolded protein response (UPR)-signalling pathway, with increased ATF4 expression and direct binding of ATF4 to FUT1 promoter in driving its transcriptional activity.

FUT1 overexpression is an important mediator in enhancing tumour growth, self-renewal and drug resistance. Its overexpression can be considered as a prognostic indicator for poor-risk HCC.

Specifically, FUT1 overexpression in HCC cells resulted in a 2.5- to 2.7-fold increase in the frequency of TICs on in vitro limiting-diluting assay, as well as enhanced cellular resistance against sorafenib on flow cytometry, with worse tumour-free survival observed in HCC cells with vs without FUT1 overexpression.

Likewise, inhibition of endogenous FUT1 expression in immunocompetent mice significantly reduced tumour initiation and self-renewal.

In addition, inhibition of α-(1,2)-fucoslyation by 2-deoxy-D-galactose (2DGal), a specific inhibitor of fucoglyprotein synthesis, sensitized HCC cells to sorafenib and thus enhanced its efficiency and efficacy, and preferentially eradicated the TIC subset of tumour.

Four cell surface proteins, namely, CD147, ICAM-1, EGFR and EPHA2, were found to be related to PI3K/AKT signalling pathways on integrated fucosylated-peptide screening and protein profiling. Aberrant α-(1,2)-fucoslyation of these cell surface proteins by FUT1 was shown to play a critical role in driving cancer stemness in response to glucose-deprivation microenvironment.