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The transcription factor ChREBP Orchestrates liver carcinogenesis by coordinating the PI3K/AKT signaling and cancer metabolism

Author

Listed:
  • Emmanuel Benichou

    (Université Paris Cité, Institut Cochin, INSERM, CNRS)

  • Bolaji Seffou

    (Université Paris Cité, Institut Cochin, INSERM, CNRS)

  • Selin Topçu

    (Université Paris Cité, Institut Cochin, INSERM, CNRS)

  • Ophélie Renoult

    (Nantes Université, INSERM U1307, CNRS 6075)

  • Véronique Lenoir

    (Université Paris Cité, Institut Cochin, INSERM, CNRS)

  • Julien Planchais

    (Université Paris Cité, Institut Cochin, INSERM, CNRS)

  • Caroline Bonner

    (Institut Pasteur de Lille
    INSERM
    European Genomic Institute for Diabetes
    Université de Lille)

  • Catherine Postic

    (Université Paris Cité, Institut Cochin, INSERM, CNRS)

  • Carina Prip-Buus

    (Université Paris Cité, Institut Cochin, INSERM, CNRS)

  • Claire Pecqueur

    (Nantes Université, INSERM U1307, CNRS 6075)

  • Sandra Guilmeau

    (Université Paris Cité, Institut Cochin, INSERM, CNRS)

  • Marie-Clotilde Alves-Guerra

    (Université Paris Cité, Institut Cochin, INSERM, CNRS)

  • Renaud Dentin

    (Université Paris Cité, Institut Cochin, INSERM, CNRS
    Institut Cochin, Faculté de Médecine 3ème étage)

Abstract

Cancer cells integrate multiple biosynthetic demands to drive unrestricted proliferation. How these cellular processes crosstalk to fuel cancer cell growth is still not fully understood. Here, we uncover the mechanisms by which the transcription factor Carbohydrate responsive element binding protein (ChREBP) functions as an oncogene during hepatocellular carcinoma (HCC) development. Mechanistically, ChREBP triggers the expression of the PI3K regulatory subunit p85α, to sustain the activity of the pro-oncogenic PI3K/AKT signaling pathway in HCC. In parallel, increased ChREBP activity reroutes glucose and glutamine metabolic fluxes into fatty acid and nucleic acid synthesis to support PI3K/AKT-mediated HCC growth. Thus, HCC cells have a ChREBP-driven circuitry that ensures balanced coordination between PI3K/AKT signaling and appropriate cell anabolism to support HCC development. Finally, pharmacological inhibition of ChREBP by SBI-993 significantly suppresses in vivo HCC tumor growth. Overall, we show that targeting ChREBP with specific inhibitors provides an attractive therapeutic window for HCC treatment.

Suggested Citation

  • Emmanuel Benichou & Bolaji Seffou & Selin Topçu & Ophélie Renoult & Véronique Lenoir & Julien Planchais & Caroline Bonner & Catherine Postic & Carina Prip-Buus & Claire Pecqueur & Sandra Guilmeau & Ma, 2024. "The transcription factor ChREBP Orchestrates liver carcinogenesis by coordinating the PI3K/AKT signaling and cancer metabolism," Nature Communications, Nature, vol. 15(1), pages 1-29, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45548-w
    DOI: 10.1038/s41467-024-45548-w
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