LncRNA-p21 Alters the Antiandrogen Enzalutamide-induced Prostate Cancer Neuroendocrine Differentiation Via Modulating the EZH2/STAT3 Signaling

Overview

Journal Nat Commun

Specialty Biology

Date 2019 Jun 14

PMID 31189930

Citations 100

Authors

Jie Luo

Keliang Wang

Shuyuan Yeh

Yin Sun

Liang Liang

Yao Xiao

Wanhai Xu

Yuanjie Niu

Liang Cheng

Sankar N Maity

Runze Jiang

Chawnshang Chang

Affiliations

Soon will be listed here.

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.

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