Disrupting androgen receptor signaling induces Snail-mediated epithelial-mesenchymal plasticity in prostate cancer

Lu Miao, Lin Yang, Rui Li, Daniel N. Rodrigues, Mateus Crespo, Jer Tsong Hsieh, Wayne D. Tilley, Johann De Bono, Luke A. Selth, Ganesh V. Raj

Research output: Contribution to journalArticle

18 Scopus citations

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 derepression of Snail and induction of EMP is an adaptive response to enzalutamide with implications for therapy resistance.

Original languageEnglish (US)
Pages (from-to)3101-3112
Number of pages12
JournalCancer Research
Volume77
Issue number11
DOIs
StatePublished - Jun 1 2017

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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