MP16-09 THE ANDROGEN RECEPTOR REPRESSES PROSTATE CANCER INVASION INDUCED BY ONCOMETABOLITE R-2-HYDROXYGLUTARATE THROUGH CIRC51217/MIR-646/TGFβ1/P-SMAD2/3 SIGNALING

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology I (MP16)1 Apr 2020MP16-09 THE ANDROGEN RECEPTOR REPRESSES PROSTATE CANCER INVASION INDUCED BY ONCOMETABOLITE R-2-HYDROXYGLUTARATE THROUGH CIRC51217/MIR-646/TGFβ1/P-SMAD2/3 SIGNALING Hua Xu* and Ding-wei Ye Shanghai Hua Xu*Hua Xu* More articles by this author and Ding-wei Ye ShanghaiDing-wei Ye Shanghai More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000841.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: IDH1 (Isocitrate dehydrogenase 1) mutation occurring at codon 132 (R132) in prostate cancer (PCa) is considered as a classifier for a subgroup PCa with accumulation of oncometabolite R-2HG (R-2-hydroxyglutarate). Besides its association with early onset of PCa, little is known about the biological effect of IDH1 mutation and R-2HG in PCa. In this study, we focus on the biological effect of IDH1 R132H mutation, which is the most frequent hotspot mutation, and oncometabolite R-2HG in PCa cell invasion. METHODS: A retrospective cohort of 1012 PCa patients in Fudan University Shanghai Cancer Center were included for next-generation sequencing. IDH1 R132H mutation was discovered as a hot spot mutation for further research. The in vitro study was designed to explore the biological function of IDH1 R132H mutation as well as R-2HG in PCa. Transwell assay was applied to test the cell invasiveness of PC3 and C4-2 PCa cell lines. CircRNA and microRNA candidates were screened based on database and manipulation of their expression was used test their function in the signaling pathway. RESULTS: Based on the next-generation sequencing data from a retrospective cohort of 1012 PCa patients, IDH1 R132H was found to be on the most frequent mutations. We discovered 9 PCa patients (0.9%) carried IDH1 R132H mutation. In the in vitro study, we found that over-expressing mutant IDH1 R132H as well as R-2HG promotes cell invasion in PCa with negative or low expression of androgen receptor (AR). Mechanism dissection revealed that R-2HG can induce circ51217 generation through increasing N6-methyladenosine (m6A) level of TGFβ1 (Transforming growth factor-β 1) mRNA, and in turn sponge miR-646 to further increase TGFβ1 protein expression and TGFβ1/p-Smad2/3 signaling. AR can suppress R-2HG effect at multiple levels, namely repressing TGFβ1 transcription and inhibiting circ51217generation via regulating ADAR2 (Double-stranded RNA-specific editase 1) expression. Preclinical study with in vivo xenograft mouse model also shows that PCa with IDH1 R132H mutation is more invasive in experimental metastasis. CONCLUSIONS: This study demonstrates that IDH1 R132H mutation as well as oncometabolite R-2HG increases cell invasiveness of PCa with negative or low expression of AR through circ51217/miR-646/TGFβ1/p-Smad2/3 signaling. AR can negate R-2HG effect via suppressing transcription of TGFβ1 and generation of circ51217. Source of Funding: National Natural Science Foundation of China (No. 81472377 and 81802570) © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e217-e217 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Hua Xu* More articles by this author Ding-wei Ye Shanghai More articles by this author Expand All Advertisement PDF downloadLoading ...