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 3

FUT1 overexpression is tightly associated with aggressive clinical features.

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FUT1 overexpression is tightly associated with aggressive clinical feat...
(A) Box-and-whisker plot analysis of FUT1 mRNA levels in nontumor (NT) liver or normal liver and HCC tissues using information gathered from the GSE14520 data set from the NCBI Gene Expression Omnibus (GEO) (left) or The Cancer Genome Atlas (TCGA) Liver Hepatocellular Carcinoma (LIHC) database (right) revealed FUT1 to be frequently overexpressed in HCC (unpaired Student’s t test). (B–D) FUT1 overexpression in HCC correlated significantly with multinodular tumors (B), advanced TNM stage (C), and worse overall survival (D) (unpaired Student’s t test, 1-way ANOVA, and Kaplan-Meier survival curve using the log-rank test, respectively). (E) FUT1 immunostaining on a tissue microarray comprising 61 paired NT liver and HCC tissue samples found FUT1 to be frequently overexpressed in HCC. Representative images of immunostaining in 2 patients are shown. Scale bar: 50 μm. The bar graph shows the percentage of cases displaying no, low, medium, and high staining intensity of FUT1 in paired NT and HCC samples (Fisher’s exact test). The dot plot illustrates the quantification of FUT1 by ImageJ (NIH), with both the intensity (mean OD) and number of cells according to the number of nuclei taken into consideration (paired Student’s t test). Mean OD per cell indicates mean OD relative to the number of nuclei. **P < 0.01; ***P < 0.001; ****P < 0.0001.