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Nicotinamide metabolism regulates glioblastoma stem cell maintenance
Jinkyu Jung, … , Stephen C. Mack, Jeremy N. Rich
Jinkyu Jung, … , Stephen C. Mack, Jeremy N. Rich
Published May 18, 2017
Citation Information: JCI Insight. 2017;2(10):e90019. https://doi.org/10.1172/jci.insight.90019.
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Research Article Oncology Stem cells

Nicotinamide metabolism regulates glioblastoma stem cell maintenance

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Abstract

Metabolic dysregulation promotes cancer growth through not only energy production, but also epigenetic reprogramming. Here, we report that a critical node in methyl donor metabolism, nicotinamide N-methyltransferase (NNMT), ranked among the most consistently overexpressed metabolism genes in glioblastoma relative to normal brain. NNMT was preferentially expressed by mesenchymal glioblastoma stem cells (GSCs). NNMT depletes S-adenosyl methionine (SAM), a methyl donor generated from methionine. GSCs contained lower levels of methionine, SAM, and nicotinamide, but they contained higher levels of oxidized nicotinamide adenine dinucleotide (NAD+) than differentiated tumor cells. In concordance with the poor prognosis associated with DNA hypomethylation in glioblastoma, depletion of methionine, a key upstream methyl group donor, shifted tumors toward a mesenchymal phenotype and accelerated tumor growth. Targeting NNMT expression reduced cellular proliferation, self-renewal, and in vivo tumor growth of mesenchymal GSCs. Supporting a mechanistic link between NNMT and DNA methylation, targeting NNMT reduced methyl donor availability, methionine levels, and unmethylated cytosine, with increased levels of DNA methyltransferases, DNMT1 and DNMT3A. Supporting the clinical significance of these findings, NNMT portended poor prognosis for glioblastoma patients. Collectively, our findings support NNMT as a GSC-specific therapeutic target in glioblastoma by disrupting oncogenic DNA hypomethylation.

Authors

Jinkyu Jung, Leo J.Y. Kim, Xiuxing Wang, Qiulian Wu, Tanwarat Sanvoranart, Christopher G. Hubert, Briana C. Prager, Lisa C. Wallace, Xun Jin, Stephen C. Mack, Jeremy N. Rich

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Figure 1

Overexpression of NNMT in glioblastoma.

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Overexpression of NNMT in glioblastoma.
(A) Fold-change (log2) of metabo...
(A) Fold-change (log2) of metabolic gene expression between glioblastoma and nontumor specimens in the TCGA GBM microarray dataset. (B) Top 10% of genes overexpressed in glioblastomas vs. nontumor samples in 6 glioblastoma expression databases cross-referenced with top 1% of genes overexpressed in glioblastomas vs. nontumor samples from the TCGA dataset by the unsupervised analysis tool in Oncomine. (C) Fold-change of NNMT mRNA expression between glioblastoma (GBM) and nontumor brain (NT) in glioblastoma expression datasets. Sample sizes as indicated on the figure. (D) Representative images of patient glioblastoma tissues with NNMT staining, out of 2 total experiments. Frozen glioblastoma sections were stained with anti-NNMT antibody and DAPI. Scale bars: 75 μm and 25 μm, respectively. (E) Waterfall plot of correlation between NNMT mRNA expression and cancer or neural precursor methylation signature scores in the TCGA GBM microarray dataset. Spearman correlation coefficients with FDR-adjusted P < 0.001 and R > 0.2 or R < –0.2 were considered significant.

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