LncRNA-p21 alters the antiandrogen enzalutamide-induced prostate cancer neuroendocrine differentiation via modulating the EZH2/STAT3 signaling

Jie Luo,Liang Liang,Chawnshang Chang,Shuyuan Yeh,Yao Xiao,Sankar N Maity,Runze Jiang,Yin Sun,Wanhai Xu,Yuanjie Niu,Keliang Wang,Liang Cheng

doi:10.1038/s41467-019-09784-9

Abstract

While the antiandrogen enzalutamide (Enz) extends the castration resistant prostate cancer (CRPC) patients’ survival an extra 4.8 months, it might also result in some adverse effects via inducing the neuroendocrine differentiation (NED). Here we found that lncRNA-p21 is highly expressed in the NEPC patients derived xenograft tissues (NEPC-PDX). Results from cell lines and human clinical sample surveys also revealed that lncRNA-p21 expression is up-regulated in NEPC and Enz treatment could increase the lncRNA-p21 to induce the NED. Mechanism dissection revealed that Enz could promote the lncRNA-p21 transcription via altering the androgen receptor (AR) binding to different androgen-response-elements, which switch the EZH2 function from histone-methyltransferase to non-histone methyltransferase, consequently methylating the STAT3 to promote the NED. Preclinical studies using the PDX mouse model proved that EZH2 inhibitor could block the Enz-induced NED. Together, these results suggest targeting the Enz/AR/lncRNA-p21/EZH2/STAT3 signaling may help urologists to develop a treatment for better suppression of the human CRPC progression.

Highlights

While the antiandrogen enzalutamide (Enz) extends the castration resistant prostate cancer (CRPC) patients’ survival an extra 4.8 months, it might result in some adverse effects via inducing the neuroendocrine differentiation (NED)
We first screened 75 long noncoding RNAs (lncRNAs) whose expressions are correlated with Prostate cancer (PCa) progression in the PCa adenocarcinoma patient-derived xenograft (PDX) (PDX-1334C) and neuroendocrine PCa cells (NEPC) PDX (PDX-144-13C) xenograft studies[29,30], and results revealed that many lncRNAs expression were significantly increased in the NEPC-PDX samples (Fig. 1a and Supplementary Data 1)
We detected 12 lncRNAs whose expression were most significantly increased in the NEPC-PDX samples as compared to the adenocarcinoma-PDX samples, and identified the highest expression of lncRNA-p21 in NE1.8 cells compared to LNCaP cells (Fig. 1b)

Summary

Introduction

While the antiandrogen enzalutamide (Enz) extends the castration resistant prostate cancer (CRPC) patients’ survival an extra 4.8 months, it might result in some adverse effects via inducing the neuroendocrine differentiation (NED). Preclinical studies using the PDX mouse model proved that EZH2 inhibitor could block the Enz-induced NED Together, these results suggest targeting the Enz/AR/lncRNA-p21/EZH2/STAT3 signaling may help urologists to develop a treatment for better suppression of the human CRPC progression. ADT with Enz treatment (ADT-Enz) may induce some unwanted adverse effects including development of Enz-resistance and increasing the PCa cell invasion as demonstrated in several preclinical models[2,3], as well as promoting the neuroendocrine (NE) differentiation (NED)[4,5]. Other studies suggested that lncRNA-p21 could function as a biomarker to monitor the PCa progression[18]

Methods

Results

Conclusion