Control of CDH1 and IDH1mut glioblastoma cell cycle by D-2- hydroxyglutarate

Abstract

Abstract Glioblastoma (GBM) is a prevalent and lethal primary brain tumor. Patients with the IDH1R132H (isocitrate dehydrogenase 1) mutation exhibit extended survival and aneuploidy, yet the underlying mechanisms are unclear. Here, we reveal that the accumulation of D-2-hydroxyglutarate (2-HG) produced by IDH1R132H mutation induces the degradation of Fizzy-related protein1(FZR1 or CDH1) by inhibiting prolyl hydroxylase EGLN2 activity. CDH1 levels are stabilized by α-KG and oxygen, independent of HIF-1α, through EGLN2-mediated hydroxylation. This novel mechanism represents the first instance of prolyl hydroxylation stabilizing a protein. The 2-HG-EGLN2-CDH1 axis induces mitotic arrest and cell growth inhibition, potentially contributing to the extended survival observed in patients with IDH1R132H mutant GBM.