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    NRF2-dependent transcriptional regulation unique to NRF2-addicted cancers

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    Séminaire de l'Institut Cochin

    Jeudi 6 septembre 2018 - 12h00 - Salle de conférence Rosalind Franklin, 2ème étage

     


    Hozumi Motohashi

    Institute of Development, Aging and Cancer (IDAC),
    Tohoku University, Sendai, Japan

     

     invitée par Karen Leroy

    Institut Cochin, 22 rue Méchain, 75014 Paris

     

    Résumé

     NRF2 is a potent transcription activator and plays a key role in cytoprotection.  While increased activity of NRF2 is principally beneficial for our health, highly malignant cancers are likely to exploit NRF2 to achieve aggressive proliferation and tumorigenesis and to acquire therapeutic resistance, lapsing into the state of NRF2 addiction.  To clarify contributions of NRF2 to the chromatin status and gene expression in NRF2-addicted cancers, we compared NRF2-dependent transcriptome profiles of NRF2-addicted and non-addicted non-small cell lung cancer (NSCLC) cell lines and identified a battery of NRF2 downstream effectors that are unique to NRF2-addicted cells.  To narrow down the direct NRF2 target genes, we examined genome-wide distributions of enhancer mark H3K27ac in A549 cells, which is a representative NRF2-addicted NSCLC cell line, with or without NRF2 knockdown.  We found that most of the enhancers bound by NRF2 were decreased in the H3K27ac deposition by NRF2 knockdown, suggesting that NRF2 makes a large contribution to enhancer formation in general.  Of note, most of the enhancers regulating NRF2-addicted cancer specific NRF2 target genes were not well established in normal adult human lung whereas those of canonical NRF2 target genes were well established in common.  Among the NRF2-addicted cancer-specific NRF2 target genes, we have selected a few molecules and evaluated their effectiveness as therapeutic targets.
     

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