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; Chawnshang Chang

doi:10.1038/s41467-019-09784-9

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, Chawnshang Chang

Genitourinary Medical Oncology

Research output: Contribution to journal › Article › peer-review

129 Scopus citations

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.

Original language	English (US)
Article number	2571
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-09784-9
State	Published - Dec 1 2019

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-019-09784-9

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

abstract = "While the antiandrogen enzalutamide (Enz) extends the castration resistant prostate cancer (CRPC) patients{\textquoteright} 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.",

author = "Jie Luo and Keliang Wang and Shuyuan Yeh and Yin Sun and Liang Liang and Yao Xiao and Wanhai Xu and Yuanjie Niu and Liang Cheng and Maity, {Sankar N.} and Runze Jiang and Chawnshang Chang",

note = "Funding Information: We thank Karen Wolf for help with manuscript preparation. This work was supported by NIH grants (CA122840 and CA256700), and Taiwan Department of Health Clinical Trial and Research Center of Excellence (DOH102-TD-B-111-004) to China Medical University, Taiwan. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

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doi = "10.1038/s41467-019-09784-9",

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T1 - LncRNA-p21 alters the antiandrogen enzalutamide-induced prostate cancer neuroendocrine differentiation via modulating the EZH2/STAT3 signaling

AU - Luo, Jie

AU - Wang, Keliang

AU - Yeh, Shuyuan

AU - Sun, Yin

AU - Liang, Liang

AU - Xiao, Yao

AU - Xu, Wanhai

AU - Niu, Yuanjie

AU - Cheng, Liang

AU - Maity, Sankar N.

AU - Jiang, Runze

AU - Chang, Chawnshang

N1 - Funding Information: We thank Karen Wolf for help with manuscript preparation. This work was supported by NIH grants (CA122840 and CA256700), and Taiwan Department of Health Clinical Trial and Research Center of Excellence (DOH102-TD-B-111-004) to China Medical University, Taiwan. Publisher Copyright: © 2019, The Author(s).

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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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LncRNA-p21 alters the antiandrogen enzalutamide-induced prostate cancer neuroendocrine differentiation via modulating the EZH2/STAT3 signaling

Abstract

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