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

Jie Luo, Keliang Wang, Shuyuan Yeh, Yin Sun, Liang Liang, Yao Xiao, Wanhai Xu (), Yuanjie Niu, Liang Cheng, Sankar N. Maity, Runze Jiang and Chawnshang Chang ()
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Jie Luo: University of Rochester
Keliang Wang: University of Rochester
Shuyuan Yeh: University of Rochester
Yin Sun: University of Rochester
Liang Liang: Shanxi Province People’s Hospital
Yao Xiao: University of Rochester
Wanhai Xu: The 4th Affiliated Hospital of Harbin Medical University
Yuanjie Niu: Tianjin Medical University
Liang Cheng: Indiana University
Sankar N. Maity: The University of Texas MD Anderson Cancer Center
Runze Jiang: Jiangmen Maternity and Child Health Care Hospital
Chawnshang Chang: University of Rochester

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09784-9

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