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.

Regulation of tumor cell plasticity by the androgen receptor in prostate cancer

“…Many other pathways that converge with the AR regulate EMT in CRPC, including the growth factor receptor tyrosine kinase (RTK), PTEN, notch, hedgehog, Wnt, and TMPRSS2:ERG pathways (Leshem et al 2011) and the STAT3 pathway (Karhadkar et al 2004, Acevedo et al 2007, Bisson & Prowse 2009, Mulholland et al 2012. For example, in a study by Izumi et al, the silencing of AR in LNCaP cells and PCa mouse xenograft models was shown to promote cell migration by up-regulating the CCL2-dependent STAT3 and EMT pathways.…”

Androgen receptor as a regulator of ZEB2 expression and its implications in epithelial-to-mesenchymal transition in prostate cancer

“…Several strides have been carried out to identify the factors contributing to EMT in PCa. Transforming growth factor beta (Zhu & Kyprianou 2010), nicotinamide adenine dinucleotide-dependent histone deacetylase or SIRT1 (Byles et al 2012), platelet-derived growth factor (Kong et al 2009), TMPRSS2/ERG (Leshem et al 2011), SNAI2 (SLUG) (Emadi Baygi et al 2010), DAB2IP (Xie et al 2010), Hsp27 (HSPB1) (Shiota et al 2013), and miRNAs (Ru et al 2012) have all been identified as EMT regulators in PCa. Interestingly, the majority of these factors mediate EMT via zinc finger E-box-binding protein (ZEB) family members, such as ZEB1 (dEF1 or AREB6) and ZEB2 (Smad-interacting protein 1 (SIP1)) (Gregory et al 2011).…”

Altered DNA Methylation Landscapes of Polycomb-Repressed Loci Are Associated with Prostate Cancer Progression and ERG Oncogene Expression in Prostate Cancer

“…Recent work, however, failed to confirm that TMPRSS2:ERG correlates with adverse tumor characteristics and unfavorable prognosis (10,11). Nonetheless, this fusion is a likely initiating event in prostate cancer development representing a separate etiology with unique expression and epigenetic profiles (12)(13)(14).…”