Glucose deprivation–induced aberrant FUT1-mediated fucosylation drives cancer stemness in hepatocellular carcinoma
Jane H.C. Loong, … , Jing-Ping Yun, Stephanie K.Y. Ma
Jane H.C. Loong, … , Jing-Ping Yun, Stephanie K.Y. Ma
Published April 20, 2021
Citation Information: J Clin Invest. 2021;131(11):e143377. https://doi.org/10.1172/JCI143377.
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Research Article Gastroenterology Oncology

Glucose deprivation–induced aberrant FUT1-mediated fucosylation drives cancer stemness in hepatocellular carcinoma

Abstract

Rapidly growing tumors often experience hypoxia and nutrient (e.g., glucose) deficiency because of poor vascularization. Tumor cells respond to the cytotoxic effects of such stresses by inducing molecular adaptations that promote clonal selection of a more malignant tumor-initiating cell phenotype, especially in the innermost tumor regions. Here, we report a regulatory mechanism involving fucosylation by which glucose restriction promotes cancer stemness to drive drug resistance and tumor recurrence. Using hepatocellular carcinoma (HCC) as a model, we showed that restricted glucose availability enhanced the PERK/eIF2α/ATF4 signaling axis to drive fucosyltransferase 1 (FUT1) transcription via direct binding of ATF4 to the FUT1 promoter. FUT1 overexpression is a poor prognostic indicator for HCC. FUT1 inhibition could mitigate tumor initiation, self-renewal, and drug resistance. Mechanistically, we demonstrated that CD147, ICAM-1, EGFR, and EPHA2 are glycoprotein targets of FUT1, in which such fucosylation would consequently converge on deregulated AKT/mTOR/4EBP1 signaling to drive cancer stemness. Treatment with an α-(1,2)-fucosylation inhibitor sensitized HCC tumors to sorafenib, a first-line molecularly targeted drug used for advanced HCC patients, and reduced the tumor-initiating subset. FUT1 overexpression and/or CD147, ICAM-1, EGFR, and EPHA2 fucosylation may be good prognostic markers and therapeutic targets for cancer patients.

Authors

Jane H.C. Loong, Tin-Lok Wong, Man Tong, Rakesh Sharma, Lei Zhou, Kai-Yu Ng, Hua-Jian Yu, Chi-Han Li, Kwan Man, Chung-Mau Lo, Xin-Yuan Guan, Terence K. Lee, Jing-Ping Yun, Stephanie K.Y. Ma

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Figure 6

Inhibition of α-(1,2) fucosylation by 2DGal increases the efficacy of sorafenib and eradicates tumor-initiating cells.

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Inhibition of α-(1,2) fucosylation by 2DGal increases the efficacy of so...
(A) Schematic representation of the effects of 2DGal and sorafenib on Huh7 HCC cell proliferation (10 mM 2DGal and 4 μM sorafenib) and HCC patient-derived organoids (HCC-HK P1 and HCC-HK P2, 10 mM 2DGal and 2 μM sorafenib; HCC10, 10 mM 2DGal and 4 μM sorafenib) after 72 hours. (B) CellTiter Glo analysis found that Huh7 cells with FUT1 overexpression (OE) responded to a combination of 2DGal and sorafenib more significantly than either drug alone when compared with the empty vector (EV) control (1-way ANOVA). (C) In vitro limiting-dilution assays of Huh7 cells cultured in low glucose treated with 2DGal (10 mM) (pairwise tests for differences in stem cell frequencies). (D) Western blot analysis of FUT1 expression in HCC-HK P1, HCC-HK P2, and HCC10. (E) CellTiter Glo analysis found that FUT1-expressing HCC organoids (HCC-HK P2 and HCC10) responded to a combination of 2DGal and sorafenib more significantly than either drug alone when compared with HCC-HK-P1 (1-way ANOVA). (F) Strategy for testing the effects of 2DGal and sorafenib in NRAS+AKT+SB HTVI–driven HCC immunocompetent mouse models. (G) Ex vivo limiting-dilution assay of HCC tumor cells harvested from the HTVI mouse models (pairwise tests for differences in stem cell frequencies). The data shown in B–E and G are representative of 3 independent experiments. 2DGal, 2-deoxy-D-galactose; LDA, limiting dilution assay; SB, sleeping beauty; HTVI, hydrodynamic tail vein injection; Combo, combination. *P < 0.05; **P < 0.01; ****P < 0.0001. NS, not significant.