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

Nat Chem Biol. 2013 May;9(5):300-6. doi: 10.1038/nchembio.1204. Epub 2013 Mar 3.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Epigenesis, Genetic* / genetics
  • Humans
  • Methionine / chemistry
  • Methionine / metabolism
  • Methylation
  • Models, Genetic*
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Niacinamide / analogs & derivatives
  • Niacinamide / chemistry
  • Niacinamide / metabolism
  • Nicotinamide N-Methyltransferase / metabolism*


  • Niacinamide
  • Methionine
  • NNMT protein, human
  • Nicotinamide N-Methyltransferase
  • N(1)-methylnicotinamide