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Androgen receptor reverses the oncometabolite R-2-hydroxyglutarate-induced prostate cancer cell invasion via suppressing the circRNA-51217/miRNA-646/TGFβ1/p-Smad2/3 signaling.

Authors
  • Xu, Hua1
  • Sun, Yin2
  • You, Bosen2
  • Huang, Chi-Ping3
  • Ye, Dingwei4
  • Chang, Chawnshang5
  • 1 Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; George Whipple Lab for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology, The Wilmot Cancer Center, University of Rochester, Rochester, NY, USA, 14646. , (China)
  • 2 George Whipple Lab for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology, The Wilmot Cancer Center, University of Rochester, Rochester, NY, USA, 14646.
  • 3 Sex Hormone Research Center and Department of Urology, China Medical University, Taichung, 404, Taiwan. , (China)
  • 4 Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. Electronic address: [email protected] , (China)
  • 5 George Whipple Lab for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology, The Wilmot Cancer Center, University of Rochester, Rochester, NY, USA, 14646; Sex Hormone Research Center and Department of Urology, China Medical University, Taichung, 404, Taiwan. Electronic address: [email protected] , (China)
Type
Published Article
Journal
Cancer letters
Publication Date
Mar 01, 2020
Volume
472
Pages
151–164
Identifiers
DOI: 10.1016/j.canlet.2019.12.014
PMID: 31846689
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

IDH1 (Isocitrate dehydrogenase 1) mutation occurring at codon 132 (R132) in prostate cancer (PCa) is considered as a classifier for a subgroup of PCas with accumulation of oncometabolite R-2HG (R-2-hydroxyglutarate). Here we found that adding R-2HG or the mutant IDH1 R132H could promote PCa cell invasion in androgen receptor (AR)-negative PC3 cells or suppressing the AR in AR-positive C4-2 cells. Mechanism dissection revealed that R-2HG could increase circRNA-51217 expression to sponge miRNA-646, which might then lead to increase TGFβ1 expression and thus induce TGFβ1/p-Smad2/3 signaling to increase PCa cell invasion. AR can suppress this R-2HG/circRNA-51217/miRNA-646/TGFβ1/p-Smad2/3 signaling-increased PCa cell invasion via repressing TGFβ1 transcription and inhibiting circRNA-51217 expression through regulating ADAR2 expression. Preclinical studies with an in vivo xenograft mouse model also revealed that PCa cells with the IDH1 R132H mutation have more invasive metastasis. This study demonstrates that IDH1 R132H mutation with increased oncometabolite R-2HG in PCa cells may play important roles to increase PCa cell invasion. Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.

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