Journal Article

TMPRSS2/ERG Promotes Epithelial to Mesenchymal Transition through the ZEB1/ZEB2 Axis in a Prostate Cancer Model

Kamer, Iris, Goldfinger, Naomi, Rotter, Varda, Leshem, Orit, Ben-Sasson, Shmuel, Goldstein, Ido, Cohen, Yehudit, Jacob-Hirsch, Jasmine, Madar, Shalom, Ehrlich, Marcelo, Gazit, Ephraim, Kogan-Sakin, Ira, Brosh, Ran, Loewenthal, Ron, Berger, Raanan

2011

Overview

Prostate cancer is the most common non-dermatologic malignancy in men in the Western world. Recently, a frequent chromosomal aberration fusing androgen regulated TMPRSS2 promoter and the ERG gene (TMPRSS2/ERG) was discovered in prostate cancer. Several studies demonstrated cooperation between TMPRSS2/ERG and other defective pathways in cancer progression. However, the unveiling of more specific pathways in which TMPRSS2/ERG takes part, requires further investigation. Using immortalized prostate epithelial cells we were able to show that TMPRSS2/ERG over-expressing cells undergo an Epithelial to Mesenchymal Transition (EMT), manifested by acquisition of mesenchymal morphology and markers as well as migration and invasion capabilities. These findings were corroborated in vivo, where the control cells gave rise to discrete nodules while the TMPRSS2/ERG-expressing cells formed malignant tumors, which expressed EMT markers. To further investigate the general transcription scheme induced by TMPRSS2/ERG, cells were subjected to a microarray analysis that revealed a distinct EMT expression program, including up-regulation of the EMT facilitators, ZEB1 and ZEB2, and down-regulation of the epithelial marker CDH1(E-Cadherin). A chromatin immunoprecipitation assay revealed direct binding of TMPRSS2/ERG to the promoter of ZEB1 but not ZEB2. However, TMPRSS2/ERG was able to bind the promoters of the ZEB2 modulators, IL1R2 and SPINT1. This set of experiments further illuminates the mechanism by which the TMPRSS2/ERG fusion affects prostate cancer progression and might assist in targeting TMPRSS2/ERG and its downstream targets in future drug design efforts.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Aberration / Androgens / Animals / Biology / Biomarkers / Cancer / Cell Line / Chromatin / Chromosome aberrations / Developmental biology / Disease Models, Animal / DNA microarrays / Drug development / E-cadherin / Epithelial cells / Epithelial-Mesenchymal Transition - genetics / ERG gene / Gene Fusion / Genes / Genetic Vectors - genetics / Genotype & phenotype / Growth factors / Homeodomain Proteins - metabolism / Humans / Immunomodulation / Immunoprecipitation / Interleukin 1 / Kinases / Lymphoma / Male / Malignancy / Markers / Mediation / Medical research / Medicine / Mesenchyme / Mice / Modulators / Nodules / Pathways / Phenotype / Prostate cancer / Prostatic Neoplasms - genetics / Prostatic Neoplasms - pathology / Repressor Proteins - metabolism / Rodents / Science / Senescence / Serine Endopeptidases - genetics / Serine Endopeptidases - metabolism / Signal Transduction - genetics / Stem cells / Studies / Trans-Activators - genetics / Trans-Activators - metabolism / Transcription / Transcription Factors - metabolism / Tumorigenesis / Tumors / Zinc Finger E-box Binding Homeobox 2 / Zinc Finger E-box-Binding Homeobox 1