1. LncRNA-p21 alters the antiandrogen enzalutamide-induced prostate cancer neuroendocrine differentiation via modulating the EZH2/STAT3 signaling
- Author
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Yao Xiao, Liang Liang, Yuanjie Niu, Liang Cheng, Wanhai Xu, Runze Jiang, Shuyuan Yeh, Keliang Wang, Yin Sun, Jie Luo, Chawnshang Chang, and Sankar N. Maity
- Subjects
0301 basic medicine ,Male ,General Physics and Astronomy ,02 engineering and technology ,Mice, SCID ,Antiandrogen ,urologic and male genital diseases ,Neuroendocrine differentiation ,Prostate cancer ,chemistry.chemical_compound ,Mice ,STAT3 ,lcsh:Science ,Multidisciplinary ,biology ,EZH2 ,Prostate ,Cell Differentiation ,021001 nanoscience & nanotechnology ,3. Good health ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,Neuroendocrine Tumors ,Prostatic Neoplasms, Castration-Resistant ,Benzamides ,Disease Progression ,RNA, Long Noncoding ,0210 nano-technology ,Signal Transduction ,STAT3 Transcription Factor ,medicine.drug_class ,Science ,Urological cancer ,macromolecular substances ,General Biochemistry, Genetics and Molecular Biology ,stat ,Article ,03 medical and health sciences ,Neuroendocrine Cells ,Cell Line, Tumor ,Nitriles ,Phenylthiohydantoin ,medicine ,Enzalutamide ,Animals ,Humans ,Enhancer of Zeste Homolog 2 Protein ,business.industry ,Androgen Antagonists ,General Chemistry ,medicine.disease ,Xenograft Model Antitumor Assays ,Androgen receptor ,030104 developmental biology ,chemistry ,biology.protein ,Cancer research ,lcsh:Q ,business - 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., The induction of neuroendocrine differentiation occurs in enzalutamide treated castration resistant prostate cancer. Here, the authors show that lncRNA-21 mediates enzalutamide induced neuroendocrine differentiation through EZH2/STAT axis and EZH2 inhibition suppresses this differentiation.
- Published
- 2019