title: TMPRSS2/ERG promotes epithelial to mesenchymal transition through the ZEB1/ZEB2 axis in a prostate cancer model.
abstract: 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.
authors: Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.
authors: Orit
authors: O
authors: Leshem
authors: Shalom
authors: S
authors: Madar
authors: Ira
authors: I
authors: Kogan-Sakin
authors: Iris
authors: I
authors: Kamer
authors: Ido
authors: I
authors: Goldstein
authors: Ran
authors: R
authors: Brosh
authors: Yehudit
authors: Y
authors: Cohen
authors: Jasmine
authors: J
authors: Jacob-Hirsch
authors: Marcelo
authors: M
authors: Ehrlich
authors: Shmuel
authors: S
authors: Ben-Sasson
authors: Naomi
authors: N
authors: Goldfinger
authors: Ron
authors: R
authors: Loewenthal
authors: Ephraim
authors: E
authors: Gazit
authors: Varda
authors: V
authors: Rotter
authors: Raanan
authors: R
authors: Berger
mesh_terms: D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D050939:Gene Fusion; D005822:Genetic Vectors / Q000235:genetics; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D012097:Repressor Proteins / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D018398:Homeodomain Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C486307:ZEB1 protein, human; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1; D012697:Serine Endopeptidases