title: NNMT promotes epigenetic remodeling in cancer by creating a metabolic methylation sink.
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.
authors: The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA.
authors: Olesya A
authors: OA
authors: Ulanovskaya
authors: Andrea M
authors: AM
authors: Zuhl
authors: Benjamin F
authors: BF
authors: Cravatt
mesh_terms: D044127:Epigenesis, Genetic / Q000235:genetics; D006801:Humans; D008715:Methionine / Q000737:chemistry / Q000378:metabolism; D008745:Methylation; D008957:Models, Genetic; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D050903:Nicotinamide N-Methyltransferase / Q000378:metabolism*
chemical_list: D009536:Niacinamide; D008715:Methionine; C494406:NNMT protein, human; D050903:Nicotinamide N-Methyltransferase; C024058:N(1)-methylnicotinamide