NNMT promotes epigenetic remodeling in cancer by creating a metabolic methylation sink
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Open Access
- 3 March 2013
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Chemical Biology
- Vol. 9 (5), 300-306
- https://doi.org/10.1038/nchembio.1204
Abstract
NNMT converts SAM to the stable metabolite 1-methylnicotinamide, which reduces the methylation potential of cancer cells and thereby alters their epigenetic state to heighten the expression of protumorigenic genes. Nicotinamide N-methyltransferase (NNMT) is overexpressed in a variety of human cancers, where it contributes to tumorigenesis by a mechanism that is still poorly understood. Here we show using metabolomics that NNMT impairs the methylation potential of cancer cells by consuming methyl units from S-adenosyl methionine to create the stable metabolic product 1-methylnicotinamide. As a result, NNMT-expressing cancer cells have an altered epigenetic state that includes hypomethylated histones and other cancer-related proteins combined with heightened expression of protumorigenic gene products. Our findings thus point to a direct mechanistic link between the deregulation of a metabolic enzyme and widespread changes in the methylation landscape of cancer cells.Keywords
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