MP79-14 LNCRNA-P21 ALTERS THE ANTIANDROGEN ENZALUTAMIDE-INDUCED PROSTATE CANCER NEUROENDOCRINE DIFFERENTIATION VIA MODULATING THE EZH2/STAT3 SIGNALING

Abstract

You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) IV (MP79)1 Apr 2020MP79-14 LNCRNA-P21 ALTERS THE ANTIANDROGEN ENZALUTAMIDE-INDUCED PROSTATE CANCER NEUROENDOCRINE DIFFERENTIATION VIA MODULATING THE EZH2/STAT3 SIGNALING Jie Luo*, Jialin Meng, Edward M. Messing, Jean V. Joseph, Shuyuan Yeh, and Chawnshang Chang Jie Luo*Jie Luo* More articles by this author , Jialin MengJialin Meng More articles by this author , Edward M. MessingEdward M. Messing More articles by this author , Jean V. JosephJean V. Joseph More articles by this author , Shuyuan YehShuyuan Yeh More articles by this author , and Chawnshang ChangChawnshang Chang More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000971.014AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Prostate cancer (PCa) is the most prevalent male cancer in the U.S, and the current standard androgen deprivation therapy (ADT) with the FDA-approved antiandrogen Enzalutamide (Enz, also known as MDV3100) may effectively suppress the castration resistant PCa (CRPC) and extend CRPC patients’ survival an extra 4.8 months. However, ADT with Enz treatment (ADT-Enz) may also induce some unwanted adverse effects including development of Enz-resistance and increasing the PCa cell invasion as demonstrated in several preclinical models, as well as promoting the neuroendocrine (NE) differentiation (NED). METHODS: The viabilities of cells were determined by MTT (Sigma) assays and WST-1 assays (Cayman Chemical). The wildtype (wt) or mutant (mut) lncRNA-p21 promoters were constructed into PGL3-basic plasmid (Promega) to do the luciferase assays and luciferase activity was measured by Dual-Luciferase Assay reagent (Promega). Protein-DNA complexes were detected by Chromatin immunoprecipitation (ChIP) assays. In vivo mouse models were generated by PDX implantation and treated with different compound treatments. RESULTS: Results from cell lines and human clinical sample surveys revealed that lncRNA-p21 expression is up-regulated in NE PCa and Enz treatment could increase the lncRNA-p21 to induce the NED. Mechanism dissection revealed that Enz could promote the lncRNA-p21 transcription viaaltering 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. CONCLUSIONS: In summary, our results suggest how Enz treatment can promote NED, and provide some potential therapies of using EZH2 inhibitors to target the AR/lncRNA-p21/EZH2/STAT3 axis to reduce the Enz-induced unwanted adverse effects of promoting the NED. Source of Funding: 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. © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e1221-e1221 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jie Luo* More articles by this author Jialin Meng More articles by this author Edward M. Messing More articles by this author Jean V. Joseph More articles by this author Shuyuan Yeh More articles by this author Chawnshang Chang More articles by this author Expand All Advertisement PDF downloadLoading ...