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Cancer Res. 2017 Jun 1;77(11):3101-3112. doi: 10.1158/0008-5472.CAN-16-2169. Epub 2017 Mar 16.

Disrupting Androgen Receptor Signaling Induces Snail-Mediated Epithelial-Mesenchymal Plasticity in Prostate Cancer.

Author information

1
Department of Urology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas.
2
Department of Urology, The First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Urology Institute of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
3
Division of Clinical Studies, The Institute of Cancer Research, London, United Kingdom.
4
Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.
5
Freemason's Foundation Centre for Men's Health, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.
6
Department of Urology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas. ganesh.raj@utsouthwestern.edu.

Abstract

Epithelial-to-mesenchymal plasticity (EMP) has been linked to metastasis, stemness, and drug resistance. In prostate cancer, EMP has been associated with both suppression and activation of the androgen receptor (AR) signaling. Here we investigated the effect of the potent AR antagonist enzalutamide on EMP in multiple preclinical models of prostate cancer and patient tissues. Enzalutamide treatment significantly enhanced the expression of EMP drivers (ZEB1, ZEB2, Snail, Twist, and FOXC2) and mesenchymal markers (N-cadherin, fibronectin, and vimentin) in prostate cancer cells, enhanced prostate cancer cell migration, and induced prostate cancer transformation to a spindle, fibroblast-like morphology. Enzalutamide-induced EMP required concomitant suppression of AR signaling and activation of the EMP-promoting transcription factor Snail, as evidenced by both knockdown and overexpression studies. Supporting these findings, AR signaling and Snail expression were inversely correlated in C4-2 xenografts, patient-derived castration-resistant metastases, and clinical samples. For the first time, we elucidate a mechanism explaining the inverse relationship between AR and Snail. Specifically, we found that AR directly repressed SNAI1 gene expression by binding to specific AR-responsive elements within the SNAI1 promoter. Collectively, our findings demonstrate that de-repression of Snail and induction of EMP is an adaptive response to enzalutamide with implications for therapy resistance. Cancer Res; 77(11); 3101-12. ©2017 AACR.

PMID:
28302679
DOI:
10.1158/0008-5472.CAN-16-2169
[Indexed for MEDLINE]
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