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A genetic cell context-dependent role for ZEB1 in lung cancer

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  • Ting Zhang

    (Thoracic Disease Research Unit, Cancer Center and College of Medicine, Mayo Clinic, 200 First Street SW, Stabile Building Room st8-08 Rochester, Minnesota 55905, USA
    Cancer Center and College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA)

  • Lixia Guo

    (Thoracic Disease Research Unit, Cancer Center and College of Medicine, Mayo Clinic, 200 First Street SW, Stabile Building Room st8-08 Rochester, Minnesota 55905, USA
    Cancer Center and College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA)

  • Chad J. Creighton

    (Dan Duncan Cancer Center, Baylor College of Medicine)

  • Qiang Lu

    (Mayo Clinic College of Medicine)

  • Don L. Gibbons

    (M.D. Anderson Cancer Center
    M.D. Anderson Cancer Center)

  • Eunhee S. Yi

    (Mayo Clinic)

  • Bo Deng

    (Mayo Clinic College of Medicine
    Institute of Surgery Research, Daping Hospital, Third Military Medical University)

  • Julian R. Molina

    (Mayo Clinic)

  • Zhifu Sun

    (Mayo Clinic)

  • Ping Yang

    (Mayo Clinic College of Medicine)

  • Yanan Yang

    (Thoracic Disease Research Unit, Cancer Center and College of Medicine, Mayo Clinic, 200 First Street SW, Stabile Building Room st8-08 Rochester, Minnesota 55905, USA
    Cancer Center and College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA)

Abstract

The Zinc-finger E-box-binding Homeobox-1 (ZEB1) is a transcription factor that promotes epithelial–mesenchymal transition (EMT) and acts as an oncogene in KRAS-mutated lung cancer models. Here we report that ZEB1 exerts the opposite effect in EGFR-mutated lung cancer cells, where it suppresses growth by increasing microRNA-200 targets to antagonize ERBB3, a driver of mutant EGFR-dependent cell growth. Among these targets, NOTCH1 represses ERBB3 promoter activity and the expression of ERBB3. Furthermore, we find that EGFR inhibitor treatment, which inhibits the growth of EGFR-mutated cells, induces ZEB1. Despite its growth-inhibiting effect, EGFR inhibitor-induced ZEB1 strongly promotes EMT-dependent resistance to EGFR inhibitors partially through NOTCH1, suggesting a multifunctional role for NOTCH1 in EGFR-mutated cells. These results support a previously unrecognized genetic cell context-dependent role for ZEB1 and suggest that NOTCH1 may be a useful target for treating resistance to EGFR inhibitors, especially EMT-driven resistance.

Suggested Citation

  • Ting Zhang & Lixia Guo & Chad J. Creighton & Qiang Lu & Don L. Gibbons & Eunhee S. Yi & Bo Deng & Julian R. Molina & Zhifu Sun & Ping Yang & Yanan Yang, 2016. "A genetic cell context-dependent role for ZEB1 in lung cancer," Nature Communications, Nature, vol. 7(1), pages 1-13, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12231
    DOI: 10.1038/ncomms12231
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