title: A genetic cell context-dependent role for ZEB1 in lung cancer.
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.
authors.affiliation: Thoracic Disease Research Unit, Division of Pulmonary and Critical Care Medicine, Cancer Center and College of Medicine, Mayo Clinic, 200 First Street SW, Stabile Building Room st8-08 Rochester, Minnesota 55905, USA.|Department of Biochemistry and Molecular Biology, Cancer Center and College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Thoracic Disease Research Unit, Division of Pulmonary and Critical Care Medicine, Cancer Center and College of Medicine, Mayo Clinic, 200 First Street SW, Stabile Building Room st8-08 Rochester, Minnesota 55905, USA.|Department of Biochemistry and Molecular Biology, Cancer Center and College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Lixia
authors.initials: L
authors.lastname: Guo
authors.affiliation: Dan Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.affiliation: Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Lu
authors.affiliation: Department of Thoracic Head and Neck Medical Oncology, M.D. Anderson Cancer Center, Houston, Texas 77030, USA.|Department of Molecular and Cellular Oncology, M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Don L
authors.initials: DL
authors.lastname: Gibbons
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Eunhee S
authors.initials: ES
authors.lastname: Yi
authors.affiliation: Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.|Thoracic Surgery Department, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Deng
authors.affiliation: Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Julian R
authors.initials: JR
authors.lastname: Molina
authors.affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Zhifu
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.affiliation: Thoracic Disease Research Unit, Division of Pulmonary and Critical Care Medicine, Cancer Center and College of Medicine, Mayo Clinic, 200 First Street SW, Stabile Building Room st8-08 Rochester, Minnesota 55905, USA.|Department of Biochemistry and Molecular Biology, Cancer Center and College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Yang
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D066246:ErbB Receptors / Q000378:metabolism; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1 / Q000378:metabolism; D015203:Reproducibility of Results; D012907:Smoking / Q000009:adverse effects; D023041:Xenograft Model Antitumor Assays; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000378:metabolism*
chemical_list: C117307:KRAS protein, human; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D011799:Quinazolines; D051881:Receptor, Notch1; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; C581292:ERBB3 protein, human; D066246:ErbB Receptors; D020893:Receptor, ErbB-3; D016283:Proto-Oncogene Proteins p21(ras); D000077156:Gefitinib