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

Emmanuel Benichou, Bolaji Seffou, Selin Topçu, Ophélie Renoult, Véronique Lenoir, Julien Planchais, Caroline Bonner, Catherine Postic, Carina Prip-Buus, Claire Pecqueur, Sandra Guilmeau, Marie-Clotilde Alves-Guerra and Renaud Dentin ()
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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
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

Nature Communications, 2024, vol. 15, issue 1, 1-29

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45548-w

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