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.

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.