Biomedical research institute
     
    You are here: Home / PhD program / Thesis defense / Role of the transcription factor ChREBP in hepatic carcinogenesis

    Role of the transcription factor ChREBP in hepatic carcinogenesis

     

    Emmanuel Benichou

    Friday 17th of june 2021 at 2 pm

     
    Institut Cochin
    Rosalind Franklin room
    (videoconference for the public)


    Supervisor: Renaud Dentin

    Team: Mitochondria, Bioenergetics, Metabolism and Signaling  

    Department: Endocrinology, Metabolism and Diabetes (EMD)

    Abstract

    The number of hepatocellular carcinoma (HCC) is constantly increasing in Western societies. As a matter of fact, liver cancer has become, in the past decade, the fourth leading cause of cancer death worldwide, due to its late diagnosis and resistance to classical chemotherapy treatments. In humans, the prevalence of HCC is particularly correlated with the burden of patients exhibiting metabolic syndrome, such as obesity, type 2 diabetes or hepatic steatosis. At the molecular level, it has been recently described that tumors cells have the capacity to reprogram their metabolic activities which are required to sustain cancer progression. In this context, due to its central role in the control of carbohydrate and lipid metabolism in the liver, we hypothesized that the glucose-regulated transcription factor ChREBP (Carbohydrate Responsive Element Binding Protein) may play a key role in the initiation and development of HCC. To answer this question, ChREBP was stably overexpressed in the liver of C57BL6/J mice by using the non-viral transposon gene transfer technique called "Sleeping beauty». As a result, we demonstrated for the first time that an increase in ChREBP transcriptional activity in the liver is sufficient, by itself, to initiate the development of poor prognosis HCC in mice. Mechanistically, ChREBP exerts its pro-proliferative effects by stimulating the activity of the pro-oncogenic PI3K/AKT signaling pathway, in part by directly regulating the expression of the regulatory subunit p85α of the class 1A PI3K. In addition, sustained ChREBP activation reroutes both glucose and glutamine metabolic fluxes toward de novo lipid and nucleotide biosynthesis, in order to support HCC tumor growth. As a result, ChREBP expression is systematically upregulated in 10 independent and publicly available human HCC datasets. Finally, in a context of therapeutic development, we identified and characterized the first pharmacological inhibitor of ChREBP activity that proved to be efficient in inhibiting hepatocyte proliferation and liver tumor growth. More interestingly, pharmacological inhibition of ChREBP significantly sensitizes human hepatocarcinoma cells to sorafenib induced cell apoptosis. Overall, our work therefore provides a better understanding of the mechanisms by which ChREBP is involved in hepatic carcinogenesis and brings strong evidence that ChREBP could represent a valuable therapeutic target for the development of new therapeutics during liver cancer treatment.