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 7

FUT1 regulates cancer stemness through a dysregulated AKT/mTOR/4EBP1 signaling axis.

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FUT1 regulates cancer stemness through a dysregulated AKT/mTOR/4EBP1 si...
(A) A reversed-phase protein array was performed using lysates of Huh7 HCC cells transfected with shNTC or shFUT1 (clones 544 and 565) or transfected with empty vector control or FUT1 overexpression vector. A heatmap of differentially expressed proteins is shown. (B) GSEA of high-FUT1-expressing HCC (top 50%) and low-FUT1-expressing HCC (bottom 50%) with data extracted from The Cancer Genome Atlas (TCGA) Liver Hepatocellular Carcinoma (LIHC) database showing that high FUT1 expression was significantly correlated with PI3K/AKT/mTOR signaling. (C) Western blot analysis shows enhanced p-AKT, p-mTOR, and p-4EBP1 levels in HCC cells treated with low glucose or when transduced with FUT1-overexpressing plasmid in both Huh7 and CLC13 HCC cells. Decreases in p-AKT, p-mTOR, and p-4EBP1 expression were also observed when Huh7 cells had suppressed FUT1 expression. (D) Western blot analysis shows that treatment of the FUT1-overexpressing cells with 2DGal (10 mM) attenuated FUT1, p-AKT, p-mTOR, and p-4EBP1 expression and reduced UEA-1 expression. The data shown in C and D are representative of 3 independent experiments. EV, empty vector control; HG, high glucose; LG, low glucose; NTC, nontargeting control; OE, overexpression; FDR, false discovery rate; NS, not significant; 2DGal, 2-deoxy-D-galactose.