Journal
TRANSLATIONAL ONCOLOGY
Volume 13, Issue 10, Pages -Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.tranon.2020.100819
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Funding
- NIH [R01CA188520, R21NS108065, R21HG009181]
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Background: Malignant gliomas have disproportionally high morbidity and mortality. Heterozygous mutations in the isocitrate dehydrogenase 1 (IDH1) gene are most common in glioma, resulting in predominantly arginine to histidine substitution at codon 132. Because IDH1(R132H) requires a wild-type allele to produce (D)-2-hydroxyglutarate for epigenetic reprogramming, loss of IDH1(R132H) heterozygosity is associated with glioma progression in an IDH1-wildtype-like phenotype. Although previous studies have reported that transgenic IDH1(R132H) induces the expression of nestina neural stem-cell marker, the underlying mechanism remains unclear. Furthermore, this finding seems at odds with better outcome of IDH1(R132H) glioma because of a negative association of nestin with overall survival. Methods: Gene expression was compared between IDH1(R132H)-hemizygous and IDH1(R132H)-heterozygous glioma cells under adherent and spheroid growth conditions. The results were validated for (D)-2-hydroxyglutarate responsiveness by pharmacologic agents, associations with DNA methylation by bioinformatic analysis, and associations with overall survival. Bisulfite DNA sequencing, chromatin immunoprecipitation, and pharmacological approach were used. Findings: Neural stem-cell marker genes, including CD44, NES, and PROM1, are generally downregulated in IDH-mutant gliomas and IDH1(R132H)-heterozygous spheroid growth compared respectively with IDH-wildtype gliomas and IDH1(R132H)-hemizygous spheroid growth, in agreement with their negative associations with patient outcome. In contrast, CD24 is specifically upregulated and apparently associated with better survival. CD24 and NES expression respond differentially to alteration of (D)-2-hydroxyglutarate levels. CD24 upregulation is associated with histone and DNA demethylation as opposed to hypermethylation in the downregulated genes. Interpretation: The better outcome of IDH-mutant glioma is orchestrated exquisitely through epigenetic reprogramming that directs bidirectional expression of neural stem-cell marker genes.
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