The role of epithelial–mesenchymal transition drivers ZEB1 and ZEB2 in mediating docetaxel‐resistant prostate cancer

• Published in: Molecular oncology 2017-03, Vol.11 (3), p.251-265
• Main Authors: Hanrahan, Karen, O'Neill, Amanda, Prencipe, Maria, Bugler, Jane, Murphy, Lisa, Fabre, Aurelie, Puhr, Martin, Culig, Zoran, Murphy, Keefe, Watson, R. William
• Format: Article
• Language: English
• Subjects: Analysis; Antimitotic agents; Antineoplastic agents; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Cadherins - genetics; Cell Line, Tumor; Docetaxel; Drug resistance; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition - drug effects; epithelial–mesenchymal transition; Ethylenediaminetetraacetic acid; Gene Expression Regulation, Neoplastic - drug effects; Homeodomain Proteins - analysis; Homeodomain Proteins - genetics; Humans; Male; prostate; Prostate - drug effects; Prostate - metabolism; Prostate - pathology; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Repressor Proteins - analysis; Repressor Proteins - genetics; resistance; RNA Interference; RNA, Small Interfering - genetics; Stem cells; Taxoids - pharmacology; Taxoids - therapeutic use; Up-Regulation - drug effects; ZEB1; ZEB2; Zinc Finger E-box Binding Homeobox 2; Zinc Finger E-box-Binding Homeobox 1 - analysis; Zinc Finger E-box-Binding Homeobox 1 - genetics
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.12030

Docetaxel is the main treatment for advanced castration‐resistant prostate cancer; however, resistance eventually occurs. The development of intratumoral drug‐resistant subpopulations possessing a cancer stem cell (CSC) morphology is an emerging mechanism of docetaxel resistance, a process driven by epithelial–mesenchymal transition (EMT). This study characterised EMT in docetaxel‐resistant sublines through increased invasion, MMP‐1 production and ZEB1 and ZEB2 expression. We also present evidence for differential EMT across PC‐3 and DU145 in vitro resistance models as characterised by differential migration, cell colony scattering and susceptibility to the CSC inhibitor salinomycin. siRNA manipulation of ZEB1 and ZEB2 in PC‐3 and DU145 docetaxel‐resistant sublines identified ZEB1, through its transcriptional repression of E‐cadherin, to be a driver of both EMT and docetaxel resistance. The clinical relevance of ZEB1 was also determined through immunohistochemical tissue microarray assessment, revealing significantly increased ZEB1 expression in prostate tumours following docetaxel treatment. This study presents evidence for a role of ZEB1, through its transcriptional repression of E‐cadherin to be a driver of both EMT and docetaxel resistance in docetaxel‐resistant prostate cancer. In addition, this study highlights the heterogeneity of prostate cancer and in turn emphasises the complexity of the clinical management of docetaxel‐resistant prostate cancer. This study investigated both ZEB1 and ZEB2 in docetaxel‐resistant prostate cancer and provides strong evidence for ZEB1, through its transcriptional repression of E‐cadherin to be a driver of EMT and docetaxel resistance. This was clinically validated, with patients treated with docetaxel exhibiting increased ZEB1 tumour expression. We also identified differential EMT across resistance models, thereby highlighting the heterogeneity of docetaxel‐resistant prostate cancer.