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; Yanan Yang

doi:10.1038/ncomms12231

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

Nat Commun. 2016 Jul 26:7:12231. doi: 10.1038/ncomms12231.

Authors

Ting Zhang^{1

2}, Lixia Guo^{1

2}, Chad J Creighton³, Qiang Lu⁴, Don L Gibbons^{5

6}, Eunhee S Yi⁷, Bo Deng^{4

8}, Julian R Molina⁹, Zhifu Sun¹⁰, Ping Yang⁴, Yanan Yang^{1

2}

Affiliations

¹ 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.
² Department of Biochemistry and Molecular Biology, Cancer Center and College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
³ Dan Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
⁴ Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
⁵ Department of Thoracic Head and Neck Medical Oncology, M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
⁶ Department of Molecular and Cellular Oncology, M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
⁷ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA.
⁸ Thoracic Surgery Department, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
⁹ Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota 55905, USA.
¹⁰ Division of Biomedical Statistics and Informatics, 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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Adenocarcinoma / genetics
Adenocarcinoma / pathology
Adenocarcinoma of Lung
Animals
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Resistance, Neoplasm / drug effects
Drug Resistance, Neoplasm / genetics
Epithelial-Mesenchymal Transition / drug effects
Epithelial-Mesenchymal Transition / genetics
ErbB Receptors / metabolism
Gefitinib
Gene Expression Regulation, Neoplastic / drug effects
Humans
Lung / metabolism
Lung / pathology
Lung Neoplasms / genetics*
Lung Neoplasms / pathology*
Male
Mice, Nude
MicroRNAs / genetics
MicroRNAs / metabolism
Promoter Regions, Genetic / genetics
Proto-Oncogene Proteins p21(ras) / metabolism
Quinazolines / pharmacology
Quinazolines / therapeutic use
Receptor, ErbB-3 / genetics
Receptor, ErbB-3 / metabolism
Receptor, Notch1 / metabolism
Reproducibility of Results
Smoking / adverse effects
Xenograft Model Antitumor Assays
Zinc Finger E-box-Binding Homeobox 1 / metabolism*

Substances

KRAS protein, human
MIRN200 microRNA, human
MicroRNAs
Quinazolines
Receptor, Notch1
ZEB1 protein, human
Zinc Finger E-box-Binding Homeobox 1
ERBB3 protein, human
ErbB Receptors
Receptor, ErbB-3
Proto-Oncogene Proteins p21(ras)
Gefitinib

Abstract

Publication types

MeSH terms

Substances

Grants and funding