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

Glioblastoma (GBM) is a prevalent and lethal primary brain tumor. Patients with the IDH1 ^R132H (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 IDH1 ^R132H 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 IDH1 ^R132H mutant GBM.