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.

中文翻译：

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雄激素受体通过抑制circRNA-51217 / miRNA-646 /TGFβ1/ p-Smad2 / 3信号传导，逆转了由竞争性代谢物R-2-羟基谷氨酸诱导的前列腺癌细胞的侵袭。

前列腺癌（PCa）中第132位密码子（R132）处发生的IDH1（异柠檬酸脱氢酶1）突变被认为是PCas子集的分类器，其上存在着同代谢物R-2HG（R-2-hydroxyglutarate）。在这里，我们发现添加R-2HG或突变IDH1 R132H可以促进PCa细胞侵袭雄激素受体（AR）阴性PC3细胞或抑制AR阳性C4-2细胞中的AR。机制剖析显示，R-2HG可将circRNA-51217表达增加到海绵miRNA-646，这可能导致TGFβ1表达增加，从而诱导TGFβ1/ p-Smad2 / 3信号增加PCa细胞的侵袭。通过抑制TGFβ1的转录并通过调节ADAR2的表达来抑制circRNA-51217的表达，AR可以抑制这种R-2HG / circRNA-51217 / miRNA-646 /TGFβ1/ p-Smad2 / 3信号增加PCa细胞的侵袭。使用体内异种移植小鼠模型的临床前研究还显示，具有IDH1 R132H突变的PCa细胞具有更多的侵袭性转移。这项研究表明，随着PCa细胞中竞争代谢物R-2HG的增加，IDH1 R132H突变可能在增加PCa细胞侵袭中起重要作用。