Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
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

  • Text
  • PDF
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 1

Glucose restriction promotes a liver tumor-initiating cell phenotype.

Options: View larger image (or click on image) Download as PowerPoint
Glucose restriction promotes a liver tumor-initiating cell phenotype.
Hu...
Huh7 and CLC13 HCC cells were cultured in high (4.5 g/L) or restricted/low (0.45 g/L) glucose. (A) In vitro limiting-dilution assays showed that the frequency of tumor-initiating cells increased 4-fold after culturing in low glucose (pairwise tests for differences in stem cell frequencies). (B) In vivo limiting-dilution assays found that the cells cultured in low glucose displayed an enhanced tumor incidence, expedited tumor latency, and a higher frequency of tumor-initiating cells (primary implantation, n = 15 per group; secondary implantation, n = 5 per group). (C) Strategy for mRNA profiling to identify altered transcriptomes of HCC cells grown in high- or low-glucose conditions. (D) Gene set enrichment analysis (GSEA) of differentially expressed genes identified by RNA-seq found that the PERK-mediated unfolded protein response was highly enriched in HCC cells cultured under low-glucose conditions. (E) Western blot analysis also found that GRP78, p-PERK, p-eIF2α, ATF4, and FUT1 levels were enhanced in glucose-restricted conditions and that the addition of 1 μM PERK inhibitor (PERKi) for 48 hours reversed the expression of p-PERK, p-eIF2α, ATF4, and FUT1. HG, high glucose; LG, low glucose. (F) In vitro limiting-dilution assays showed that the frequency of tumor-initiating cells increased after culture in low glucose and decreased when HCC cells cultured in low glucose were treated with PERKi (1 μM) (pairwise tests for differences in stem cell frequencies). The data shown in A, E, and F are representative of 3 independent experiments. CSC, cancer stem cell; FDR, false discovery rate. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts