Nicotinamide metabolism regulates glioblastoma stem cell maintenance

被引:92
作者
Jung, Jinkyu [1 ,5 ]
Kim, Leo J. Y. [1 ,2 ,3 ,4 ]
Wang, Xiuxing [1 ]
Wu, Qiulian [1 ]
Sanvoranart, Tanwarat [1 ]
Hubert, Christopher G. [1 ]
Prager, Briana C. [1 ,2 ,3 ,4 ]
Wallace, Lisa C. [1 ]
Jin, Xun [1 ]
Mack, Stephen C. [1 ]
Rich, Jeremy N. [1 ,2 ,6 ]
机构
[1] Cleveland Clin, Lerner Res Inst, Dept Stem Cell Biol & Regenerat Med, Cleveland, OH 44195 USA
[2] Cleveland Clin, Lerner Coll Med, Dept Mol Med, Cleveland, OH USA
[3] Case Western Reserve Univ, Sch Med, Med Scientist Training Program, Cleveland, OH USA
[4] Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44106 USA
[5] NCI, Neurooncol Branch, NIH, Bethesda, MD 20892 USA
[6] Univ Calif San Diego, Dept Med, Div Regenerat Med, San Diego, CA 92103 USA
基金
中国国家自然科学基金; 加拿大健康研究院;
关键词
RANDOMIZED PHASE-III; N-METHYLTRANSFERASE; MESENCHYMAL DIFFERENTIATION; HOMOCYSTEINE METABOLISM; METHIONINE METABOLISM; RADIATION-RESISTANCE; DNA METHYLATION; SELF-RENEWAL; NAD PLUS; CANCER;
D O I
10.1172/jci.insight.90019
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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.
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页数:23
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