Nicotinamide metabolism regulates glioblastoma stem cell maintenance

JCI Insight
Jinkyu JungJeremy N Rich

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...Continue Reading

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Citations

Oct 17, 2017·Nature Medicine·Xun JinJeremy N Rich
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Methods Mentioned

BETA
RNAseq
transfection
xenograft
PCR
ChIP-seq
ChIP-PCR
ChIP
confocal microscopy

Software Mentioned

GLAM2
MEME
Oncomine
GraphPad Prism
- DREME suite
GSEA
TOMTOM
cBioPortal
Matlab
NCSS

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