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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Androgen Antagonists / adverse effects*
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Animals
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Benzamides
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Cell Differentiation / drug effects
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Cell Differentiation / genetics
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Cell Line, Tumor
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Disease Progression
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Enhancer of Zeste Homolog 2 Protein / metabolism
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Gene Expression Regulation, Neoplastic / drug effects*
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Humans
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Male
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Mice
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Mice, SCID
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Neuroendocrine Cells / drug effects
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Neuroendocrine Cells / pathology
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Neuroendocrine Tumors / drug therapy
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Neuroendocrine Tumors / genetics
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Neuroendocrine Tumors / pathology*
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Nitriles
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Phenylthiohydantoin / adverse effects
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Phenylthiohydantoin / analogs & derivatives*
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Prostate / cytology
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Prostate / drug effects
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Prostate / pathology
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Prostatic Neoplasms, Castration-Resistant / drug therapy
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Prostatic Neoplasms, Castration-Resistant / genetics
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Prostatic Neoplasms, Castration-Resistant / pathology*
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RNA, Long Noncoding / metabolism*
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STAT3 Transcription Factor / metabolism
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Up-Regulation / drug effects
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Xenograft Model Antitumor Assays
Substances
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Androgen Antagonists
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Benzamides
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Nitriles
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RNA, Long Noncoding
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STAT3 Transcription Factor
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STAT3 protein, human
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Phenylthiohydantoin
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enzalutamide
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EZH2 protein, human
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Enhancer of Zeste Homolog 2 Protein