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

Ting Zhang, Lixia Guo, Chad J. Creighton, Qiang Lu, Don L. Gibbons, Eunhee S. Yi, Bo Deng, Julian R. Molina, Zhifu Sun, Ping Yang and Yanan Yang ()
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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
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
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
Eunhee S. Yi: Mayo Clinic
Bo Deng: Mayo Clinic College of Medicine
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

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12231

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