IDH1 mutations inhibit multiple α-ketoglutarate-dependent dioxygenase activities in astroglioma

摘要

The mechanism of tumorigenesis associated with nicotinamide adenine dinucleotide phosphate (NADP+)-dependent isocitrate dehydrogenase 1 (IDH1) mutations in gliomas is not fully understood. Loss of catalytic activity leading to a decrease in α-ketoglutarate (αKG) and gain of novel catalytic activity leading to production of d-2-hydroxylglutarate (d-2-HG) are both found in IDH1-mutated glioma cells. Both the decrease of αKG and accumulation of d-2-HG inhibit the activity of multiple dioxygenases including prolyl hydroxylase domain-2 (PHD2), collagen prolyl-4-hydroxylase, histone demethylases, and the ten–eleven translocation (TET) family of 5-methylcytosine hydroxylases. Here we correlated the products of these dioxygenases after IDH1 gene mutations with tumorigenesis in human astroglioma samples. DNA sequencing was carried out for 253 astroglioma samples to identify IDH1 mutations. Immunohistochemistry analysis was employed to verify the levels of endostatin, dimethylated H3k79 (H3k79me2), and 5-hydroxymethylcytosine (5hmC) in these astroglioma samples. IDH1 mutations occurred frequently in low grades of astrocytoma. One case bearing both IDH1 and IDH2 mutations was identified. IDH1-mutated cases displayed more frontal lobe location and p53-positive immunostaining than wild-type cases. IDH1 mutations were associated with increased histone methylation and decreased 5hmC. By inhibiting endostatin expression, IDH1 mutations indirectly promoted angiogenesis in gliomas. All these changes were same in astroglioma at different malignancy grade. IDH1 mutations showed wide regulation of angiogenesis and genome-wide change of histone and DNA methylation, which were not suppressed as the malignancy level progressed, suggesting an early role of IDH1 mutations in astrocytoma tumorigenesis.