ZEB1 Coordinately Regulates Laminin-332 and β4 Integrin Expression Altering the Invasive Phenotype of Prostate Cancer Cells

Justin M Drake; J. Matthew Barnes; Joshua M Madsen; Frederick E Domann; Christopher S Stipp; Michael D Henry

doi:10.1074/jbc.M110.136044

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ZEB1 Coordinately Regulates Laminin-332 and β4 Integrin Expression Altering the Invasive Phenotype of Prostate Cancer Cells

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ZEB1 Coordinately Regulates Laminin-332 and β4 Integrin Expression Altering the Invasive Phenotype of Prostate Cancer Cells

Justin M Drake, J. Matthew Barnes, Joshua M Madsen, Frederick E Domann, Christopher S Stipp and Michael D Henry

The Journal of biological chemistry, Vol.285(44), pp.33940-33948

10/29/2010

DOI: 10.1074/jbc.M110.136044

PMCID: PMC2962494

PMID: 20729552

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Abstract

Metastasis involves the invasion of cancer cells across both the extracellular matrix and cellular barriers, and an evolving theme is that epithelial-to-mesenchymal transition (EMT) may mediate invasive cellular behavior. Previously, we isolated and analyzed a subpopulation of PC-3 prostate cancer cells, TEM4-18, and found that these cells both invaded an endothelial barrier more efficiently and exhibited enhanced metastatic colonization in vivo . Transendothelial migration of these cells depended on expression of ZEB1, a known regulator of EMT. Surprisingly, these cells were much less invasive than parental PC-3 cells in assays that involve matrix barriers. Here, we report that TEM4-18 cells express significantly reduced levels of two subunits of laminin-332 (β3 and γ2) and that exogenous laminin-332, or co-culture with laminin-332-expressing cells, rescues the in vitro invasion phenotype in these cells. Stable knockdown of ZEB1 in prostate cancer cells up-regulated LAMC2 and ITGB4 mRNA and protein and resulted in a concomitant increase in Transwell migration. Using chromatin immunoprecipitation (ChIP), we show that ZEB1 directly interacts with the promoters of LAMC2 and ITGB4. These results provide a novel molecular basis for reduced laminin-332 observed in clinical prostate cancer specimens and demonstrate a context-dependent role for EMT in invasive cellular behavior.

Extracellular Matrix

Prostate Cancer

Cell Biology

Cell Migration

Molecular Bases of Disease

Integrin

Laminin

Epithelial Cell

Details

Title: Subtitle: ZEB1 Coordinately Regulates Laminin-332 and β4 Integrin Expression Altering the Invasive Phenotype of Prostate Cancer Cells
Creators: Justin M Drake - From the Departments of
J. Matthew Barnes - From the Departments of
Joshua M Madsen - Radiation Oncology, Roy J. and Lucille A. Carver College of Medicine
Frederick E Domann - Radiation Oncology, Roy J. and Lucille A. Carver College of Medicine
Christopher S Stipp - the
Michael D Henry - From the Departments of
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.285(44), pp.33940-33948
DOI: 10.1074/jbc.M110.136044
PMID: 20729552
PMCID: PMC2962494
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: American Society for Biochemistry and Molecular Biology; 9650 Rockville Pike, Bethesda, MD 20814, U.S.A
Grant note: R01 CA130916; R01 CA136664; R01 CA115438 / National Institutes of Health
Alternative title: ZEB1 Regulates Mode of Cell Invasion
Language: English
Date published: 10/29/2010
Academic Unit: Molecular Physiology and Biophysics; Pathology; Surgery; Biology; Radiation Oncology; Urology
Record Identifier: 9984047705502771

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