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IDH1 R132H Causes Resistance to HDAC Inhibitors by Increasing NANOG in Glioblastoma Cells

IDH1 R132H Causes Resistance to HDAC Inhibitors by Increasing NANOG in Glioblastoma Cells

Geon-Hee Kim, So Young Choi, Taek-In Oh, Sang-Yeon Kan, Hyeji Kang, Sujin Lee, Taerim Oh, Hyun Myung Ko, Ji-Hong Lim

Int J Mol Sci. 2019 May 31;20(11):2679.

PMID: 31151327

Abstract:

The R132H mutation in isocitrate dehydrogenase 1 (IDH1R132H) is commonly observed and associated with better survival in glioblastoma multiforme (GBM), a malignant brain tumor. However, the functional role of IDH1R132H as a molecular target for GBM treatment is not completely understood. In this study, we found that the overexpression of IDH1R132H suppresses cell growth, cell cycle progression and motility in U87MG glioblastoma cells. Based on cell viability and apoptosis assays, we found that IDH1R132H-overexpressing U87MG and U373MG cells are resistant to the anti-cancer effect of histone deacetylase inhibitors (HDACi), such as trichostatin A (TSA), vorinostat (SAHA), and valproic acid. Octyl-(R)-2-hydroxyglutarate (Octyl-2HG), which is a membrane-permeable precursor form of the oncometabolite (R)-2-hydroxyglutarate (R-2HG) produced in IDH1-mutant tumor cells, significantly increased HDACi resistance in glioblastoma cells. Mechanistically, IDH1R132H and Octyl-2HG enhanced the promoter activation of NANOG via increased H3K4-3Me, consequently increasing NANOG mRNA and protein expression. Indeed, HDACi resistance was attenuated in IDH1R132H-expressing glioblastoma cells by the suppression of NANOG using small interfering RNAs. Furthermore, we found that AGI-5198, a selective inhibitor of IDH1R132H, significantly attenuates HDACi resistance and NANOG expression IDH1R132H-expressing glioblastoma cells. These results suggested that IDH1R132H is a potential molecular target for HDACi-based therapy for GBM.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1355326350	AGI-5198		1355326-35-0	Price
AP1391194674	Octyl-(R)-2HG		1391194-67-4	Price

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