@article{a65b3ae728e047ffa741d674991204fe,
title = "Differential expression of the TWEAK receptor Fn14 in IDH1 wild-type and mutant gliomas",
abstract = "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.",
keywords = "DNA methylation, Fn14, Glioblastoma, IDH, TWEAK, Tumor subtypes",
author = "Hersh, {David S.} and Sen Peng and Dancy, {Jimena G.} and Rebeca Galisteo and Eschbacher, {Jennifer M.} and Castellani, {Rudy J.} and Heath, {Jonathan E.} and Teklu Legesse and Kim, {Anthony J.} and Woodworth, {Graeme F.} and Tran, {Nhan L.} and Winkles, {Jeffrey A.}",
note = "Funding Information: Fig. 5 Analysis of Fn14 protein expression in IDH1 R132H-over-expressing glioma cells and the effect of the IDH R132H inhibitor AGI-5198 or the demethylation agent 5-aza-dC on Fn14 levels. a Stably-transfected U138 and LN18 glioma cell lines were harvested and IDH1 R132H, Fn14 and GAPDH levels were evaluated by Western blot analysis. b LN18 IDH1 R132H cells were either treated with vehicle (DMSO) or 1 µM AG-5198 for the indicated number of days. Cells were harvested and Fn14, PAR-4 and GAPDH levels were evaluated by Western blot analysis. c LN18 IDH1 R132H cells were either treated with vehicle (DMSO) or three doses of 5-aza-dC for 3 days. Cells were harvested and Fn14, MLH1 and GAPDH levels were evaluated by Western blot analysis Acknowledgements We thank Dr. Craig Horbinski for providing the glioma cell lines. We also thank Ashley Cellini and Kimberly Tuttle for their assistance with obtaining tissue slides from the University of Maryland Greenebaum Cancer Center{\textquoteright}s Pathology and Biorepository Shared Service. This work was supported in part by National Institutes of Health Grant K08 NS09043 (G.F.W.), American Cancer Society Research Scholar Grant 128970-RSG-16-012-01-CDD (G.F.W.), and The Ben and Catherine Ivy Foundation (N.L.T.). J.G.D. was supported by the NIH T32 Training Grant CA154274 and an NIGMS Initiative for Maximizing Student Development Grant (R25 GM55036).",
year = "2018",
month = jun,
day = "1",
doi = "10.1007/s11060-018-2799-3",
language = "English (US)",
volume = "138",
pages = "241--250",
journal = "Journal of Neuro-Oncology",
issn = "0167-594X",
publisher = "Kluwer Academic Publishers",
number = "2",
}