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: Olesya A Ulanovskaya, Andrea M Zuhl, Benjamin F Cravatt
• Journal: Nature chemical biology (Nat Chem Biol) Vol. 9 Issue 5 Pg. 300-6 (May 2013) ISSN: 1552-4469 [Electronic] United States
• PMID: 23455543 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

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

Topics

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