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

Nicotinamide N-methyltransferase (NNMT) is overexpressed in a variety of human cancers, where it contributes to tumorigenesis by a still poorly understood mechanism. 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 possess an altered epigenetic state that includes hypomethylated histones and other cancer-related proteins combined with heightened expression of pro-tumorigenic 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.