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.
View: Text | PDF
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

×

Figure 2

The PERK-mediated unfolded protein response activates FUT1 promoter activity via ATF4 induction under glucose restriction.

Options: View larger image (or click on image) Download as PowerPoint
The PERK-mediated unfolded protein response activates FUT1 promoter acti...
(A) A volcano plot revealed the top 3 most significantly enhanced genes when HCC cells were cultured in low glucose. (B) Analysis of FUT1 and ATF4 expression in The Cancer Genome Atlas (TCGA) Liver Hepatocellular Carcinoma (LIHC) database (unpaired Student’s t test and Pearson’s correlation test). (C) FUT1 expression in low-glucose culturing conditions was validated by qPCR in Huh7 and CLC13 cells and HCC patient–derived spheroids (unpaired Student’s t test). The data shown are representative of 3 independent experiments. (D) Confirmation of ATF4 binding to both predicted sites on FUT1 by ChIP-qPCR using anti-ATF4 and control IgG antibodies (unpaired Student’s t test and 1-way ANOVA). The data shown are representative of at least 3 independent experiments. (E) Luciferase reporter assays found that only ATF4 binding site 2 (Δ3′) was critical in modulating FUT1 transcriptional activity and FUT1 transcriptional activity was upregulated under glucose-deprived conditions in Huh7 and CLC13 HCC cells. ATF4 expression was induced by low-glucose treatment (unpaired Student’s t test and 1-way ANOVA). The data shown are representative of 3 independent experiments. HG, high glucose; LG, low glucose; FL, full-length. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.