The
TNF receptor superfamily member Fn14 is overexpressed by many solid
tumor types, including
glioblastoma (GBM), the most common and lethal form of adult
brain cancer. GBM is notable for a highly infiltrative growth pattern and several groups have reported that high Fn14 expression levels can increase
tumor cell invasiveness. We reported previously that the mesenchymal and proneural GBM transcriptomic subtypes expressed the highest and lowest levels of Fn14
mRNA, respectively. Given the recent histopathological re-classification of human
gliomas by the World Health Organization based on
isocitrate dehydrogenase 1 (IDH1) gene mutation status, we extended this work by comparing Fn14 gene expression in IDH1 wild-type (WT) and mutant (R132H)
gliomas and in cell lines engineered to overexpress the IDH1 R132H
enzyme. We found that both low-grade and high-grade (i.e., GBM) IDH1 R132H
gliomas exhibit low Fn14
mRNA and
protein levels compared to IDH1 WT
gliomas. Forced overexpression of the IDH1 R132H
protein in
glioma cells reduced Fn14 expression, while treatment of IDH1 R132H-overexpressing cells with the IDH1 R132H inhibitor
AGI-5198 or the
DNA demethylating agent
5-aza-2'-deoxycytidine increased Fn14 expression. These results support a role for Fn14 in the more aggressive and invasive phenotype associated with IDH1 WT
tumors and indicate that the low levels of Fn14 gene expression noted in IDH1 R132H mutant
gliomas may be due to epigenetic regulation via changes in DNA methylation.