MP16-06 PUTATIVE TUMOR SUPPRESSOR ELL2 IS REQUIRED FOR PROLIFERATION AND SURVIVAL OF AR-NEGATIVE PROSTATE CANCER CELLS

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology I (MP16)1 Apr 2020MP16-06 PUTATIVE TUMOR SUPPRESSOR ELL2 IS REQUIRED FOR PROLIFERATION AND SURVIVAL OF AR-NEGATIVE PROSTATE CANCER CELLS Zhi Wang*, Laura E. Pascal, Uma R Chandran, Srilakshmi Chaparala, Shidong Lyu, Ding Hui, Lin Qi, and Zhou Wang Zhi Wang*Zhi Wang* More articles by this author , Laura E. PascalLaura E. Pascal More articles by this author , Uma R ChandranUma R Chandran More articles by this author , Srilakshmi ChaparalaSrilakshmi Chaparala More articles by this author , Shidong LyuShidong Lyu More articles by this author , Ding HuiDing Hui More articles by this author , Lin QiLin Qi More articles by this author , and Zhou WangZhou Wang More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000841.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Elongation Factor For RNA Polymerase II, 2 (ELL2) was reported as a putative tumor suppressor in the prostate cancer. ELL2 is frequently down-regulated in prostatic adenocarcinoma specimens. Loss of ELL2 induced murine prostatic intraepithelial neoplasia and enhanced AR-positive prostate cancer cell proliferation. However, ELL2 gene was amplified or overexpressed in neuroendocrine prostate tumors, suggesting a potential oncogenic role for ELL2 in AR-negative neuroendocrine prostate cancer cells. In this study, we explored potential function of ELL2 in PC3 and DU145, two AR-negative prostate cancer cells with some neuroendocrine phenotype. METHODS: The role of ELL2 in PC3 and DU145 was studied by determining the impact of ELL2 knockdown. Genes regulated by ELL2 knockdown in PC3 cells was identified using RNA-Seq and bioinformatics. Expression of various genes were confirmed by western blot and quantitative real-time PCR. Cell growth were determined by BrdU, MTT and colony formation assays. The cell death was analyzed by Annexin V/7-AAD staining. Cell cycle was determined by flow cytometry. RESULTS: ELL2 knockdown inhibited proliferation in PC3 and DU145 cells, in contrast to the enhancement of proliferation in AR-positive LNCaP and C4-2 prostate cancer cells by ELL2 knockdown. RNA-Seq analysis showed an enrichment in genes associated with cell death and survival following ELL2 knockdown. The interferon-γ pathway was identified as the top canonical pathway comprising of 55.6% of the differentially expressed genes. ELL2 knockdown induced an increase in STAT1 and IRF1 mRNA and an induction of total STAT1 and phosphorylated STAT1 protein. Inhibition of cell proliferation by ELL2 knockdown was partly abrogated by siSTAT1 knockdown. Colony formation and MTT assay suggested that ELL2 knockdown could induce profound cell death in both PC3 and DU145 cells. Flow cytometry analysis showed that knockdown ELL2 indeed induced apoptosis and also caused S-phase arrest. CONCLUSIONS: ELL2 knockdown inhibited cell proliferation, induced S-phase arrest, promoted apoptosis in AR-negative PC3 and DU145 prostate cancer cells, which is accompanied by the induction of genes associated with cell death and survival as well as the interferon-γ pathway. This suggests a potential oncogenic role for ELL2 in AR-negative prostate cancer cells. The mechanisms by which ELL2 promotes AR-negative prostate cancer cell proliferation and survival may represent potential targets for the treatment of AR-negative prostate cancer. Source of Funding: This project was supported in part by NIH grant R01 CA186780 and R50 CA211242. © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e216-e216 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Zhi Wang* More articles by this author Laura E. Pascal More articles by this author Uma R Chandran More articles by this author Srilakshmi Chaparala More articles by this author Shidong Lyu More articles by this author Ding Hui More articles by this author Lin Qi More articles by this author Zhou Wang More articles by this author Expand All Advertisement PDF downloadLoading ...