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NNMT promotes epigenetic remodeling in cancer by creating a metabolic methylation sink

Nature Chemical Biology volume 9, pages 300–306 (2013)Cite this article

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Abstract

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.

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Figure 1: NNMT is elevated in aggressive human cancer cells.
Figure 2: Structural assignment of 1MNA and SAH as deregulated metabolites in NNMT-OE cells.
Figure 3: NNMT regulates SAM and SAH levels in cancer cells.
Figure 4: NNMT regulates the methylation state of histones and other signaling proteins in cancer cells.

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Acknowledgements

This work was supported by the US National Institutes of Health (CA132630), a postdoctoral fellowship from Bayer (O.A.U.) and an US National Science Foundation predoctoral fellowship (A.M.Z.).

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Authors and Affiliations

  1. The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA

    Olesya A Ulanovskaya, Andrea M Zuhl & Benjamin F Cravatt

  2. Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA

    Olesya A Ulanovskaya, Andrea M Zuhl & Benjamin F Cravatt

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  1. Olesya A Ulanovskaya
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Contributions

O.A.U. and B.F.C. designed the experiments, analyzed the data and wrote the manuscript. A.M.Z. synthesized 1MNA and d4-1MNA. O.A.U. performed all other experiments.

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Correspondence to Benjamin F Cravatt.

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The authors declare no competing financial interests.

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Ulanovskaya, O., Zuhl, A. & Cravatt, B. NNMT promotes epigenetic remodeling in cancer by creating a metabolic methylation sink. Nat Chem Biol 9, 300–306 (2013). https://doi.org/10.1038/nchembio.1204

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