Androgen receptor regulates eIF5A2 expression and promotes prostate cancer metastasis via EMT

Yuancai Zheng,Wei Chen,Xueting Ye,Hang Huang,Ping Li,Guodong Xu,Fangyi Zhang

doi:10.1038/s41420-021-00764-x

Abstract

Androgen receptor (AR) is an androgen-activated transcription factor of the nuclear receptor superfamily. AR plays a role in the development and progression of prostate cancer (PCa). However, the exact role of AR in PCa metastasis remains unclear. In the present study, we aimed to elucidate the function of AR in PCa. We found that eukaryotic translation initiation factor (EIF) 5A2, an elongation factor that induces epithelial-to-mesenchymal transition (EMT) in PCa cells, was significantly upregulated after 5α-dihydrotestosterone (DHT) stimulation and downregulated after anti‐androgen bicalutamide treatment in PCa cells with high AR expression, but not in cells with low AR expression. Moreover, eIF5A2 knockdown could eliminate DHT-induced invasion and migration of AR-positive PCa cells. DHT treatment decreased epithelial expression of E‐cadherin and β-catenin but increased the expression of the mesenchymal marker proteins Vimentin and N-cadherin. DHT therefore induced EMT, and knockdown of eIF5A2 inhibited DHT-induced EMT. Moreover, in vivo study, Luciferase signals from the lungs of the eIF5A2 plasmid group indicated higher metastasis ability, and the eIF5A2 siRNA group had lower metastasis ability. Our results suggest that AR positively regulates eIF5A2 expression in androgen-dependent cells, and stimulation of AR expression and signaling in prostate tumors promotes PCa metastasis by EMT induction and upregulation of eIF5A2.

Highlights

Prostate cancer (PCa) is the most common cancer among men worldwide [1]
Androgen regulates the expression of Eukaryotic translation initiation factor 5A2 (eIF5A2) in PCA cells in an androgen receptor (AR)-dependent manner To study the interaction between eIF5A2 and AR, we first tested the expression of eIF5A2 in 4 PCa cell lines
EIF5A2 mRNA is upregulated in several human tumor cell types such as pancreatic ductal adenocarcinoma, hepatocellular cancer, lung cancer, colorectal cancer, and gastric cancer, indicating that eIF5A2 is a potential oncogene

Summary

Introduction

Prostate cancer (PCa) is the most common cancer among men worldwide [1]. Androgens are essential to the development and progression of PCa [2], and androgen deprivation therapy (ADT) is currently the predominant treatment for locally advanced or metastatic PCa [3]. AR alters the expression of its downstream genes by interacting with coregulators, including activators and repressors, thereby regulating the transcription of androgen response genes, which play a crucial role in prostate cancer metastasis [4, 5]. The identification and characterization of the androgen-responsive genes, which are crucial for hormonestimulated cancer growth, could lead to the discovery and development of new therapeutic targets and more effective therapies. Eukaryotic translation initiation factor 5A2 (eIF5A2), an isoform of eIF5A, plays an essential role in mRNA translation [6], and is an oncogene that regulates cell proliferation, invasion, metastasis, and cancer progression in several cancers [7,8,9,10]. EIF5A2 overexpression in prostate cancer cells a potential prognostic predictive factor and therapeutic target [17]. The exact role of eIF5A2 in PCa progression is unclear

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