Glucose deprivation–induced aberrant FUT1-mediated fucosylation drives cancer stemness in hepatocellular carcinoma
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
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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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 8

CD147, ICAM-1, EGFR, and EPHA2 are mediators of FUT1 that regulate cancer stemness via the AKT/mTOR/4EBP1 signaling axis.

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CD147, ICAM-1, EGFR, and EPHA2 are mediators of FUT1 that regulate cance...
(A) Schematic representation of our experimental approach to fucosylated-peptide profiling. (B) Venn diagram showing the number of proteins identified by nano–LC MS/MS analysis of the UEA-1–enriched fractions of cells treated with empty vector control and cells with FUT1 overexpression, as well as the common proteins that matched the Cancer Stem Cell database (CSCdb; ref. 15). Of the 30 proteins, 24 are related to PI3K/AKT signaling, including 4 cell surface proteins (ICAM1, CD147, EGFR, and EPHA2). (C) UEA-1 affinity chromatography of whole-cell lysates of Huh7 HCC cells transfected with empty vector or with FUT1 overexpression and in the absence or presence of 2DGal or Huh7 HCC cells cultured in high or low glucose, followed by Western blotting with LAMP2, CD147, ICAM-1, EGFR, and EPHA2 antibodies. Input shows no effect of glucose restriction and FUT1 overexpression on protein expression. LAMP2 was used as positive control. The data shown are representative of 3 independent experiments. EV, empty vector control; OE, overexpression; HG, high glucose; LG, low glucose; 2DGal, 2-deoxy-D-galactose.