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 4

Knockdown of endogenous Fut1 expression in the liver of an immunocompetent HCC mouse model attenuates hepatocarcinogenesis.

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Knockdown of endogenous Fut1 expression in the liver of an immunocompete...
(A) Schematic representation of the hydrodynamic tail vein injection (HTVI) model in C57BL/6 mice. (B) qPCR analysis of Fut1 expression in mice that received HTVI of either empty vector control (EV CTRL) or NRAS, AKT, and sleeping beauty (SB) transposase for HCC induction with samples collected at various time points. n = 22 in total (EV, n = 3; 1 week, n = 3; 2 weeks, n =3; 3 weeks, n = 3; 4 weeks, n = 3; 5 weeks, n = 3; endpoint, n = 7) (1-way ANOVA). (C) Strategy for testing the functional significance of Fut1 in hepatocarcinogenesis. NRAS, AKT, and SB transposase were delivered by HTVI for HCC induction. Lentiviral particles with nontargeting control shRNA (shNTC) or shFut1 were administered twice at 4 and 5.5 weeks. Mice were sacrificed at 10 weeks after plasmid injection. (D) Representative images of dissected livers at the end of the experiment. Scale bars: 5 cm and 2 cm (enlarged images). Successful Fut1 knockdown confirmed by qPCR. n = 11–12 per group. (E) An ex vivo limiting-dilution assay of HCC tumor cells harvested from HTVI mouse models found that the frequency of tumor-initiating cells decreased in the mice administered shFut1 lentiviral particles. The data shown are representative of 3 independent experiments (pairwise tests for differences in stem cell frequencies). *P < 0.05.