NNMT Reduces Cellular Methylation Potential

Emerging evidence indicates that deregulation of metabolic enzymes can have widespread protumorigenic effects. Nicotinamide N-methyltransferase (NNMT) is one such enzyme that is overexpressed in many tumor types and promotes cancer cell migration, invasion, growth, and survival. NNMT is known to transfer a methyl group from S-adenosyl-L-methionine (SAM), the same methyl donor used by other methyltransferases, to nicotinamide to generate S-adenosylhomocysteine (SAH) and 1-methylnicotinamide (1MNA), but the selective advantage of this reaction in cancer cells is unknown. Ulanovskaya and colleagues profiled NNMT expression in cancer cell lines and showed that NNMT expression and 1MNA production were significantly higher in aggressive cell lines than in nonaggressive cell lines. 1MNA itself did not confer enhanced migratory properties on nonaggressive cell lines, prompting the authors to perform an unbiased metabolomic screen in NNMT-overexpressing cancer cells to determine whether NNMT caused other metabolic changes. However, other than 1MNA, the only metabolite that was consistently upregulated was SAH, the other product of NNMT catalysis. Because 1MNA was remarkably stable in cancer cells and methyl groups donated by SAM were not readily recovered, NNMT overexpression greatly decreased the SAM:SAH ratio. Given the role of SAM as a universal methyl donor, these results suggested that, by catalyzing the overproduction of a metabolite that acts as a sink for methylation units, NNMT overexpression would reduce cellular methylation potential. Indeed, NNMT overexpression led to decreases in many histone methylation events, which were associated with changes in gene expression, as well as methylation of other cellular proteins, whereas DNA methylation was unaffected. Although the basis for these selective effects on methylation remain unclear, these findings identify potential metabolic and epigenetic consequences of NNMT overexpression in cancer and further underscore the close relationship between cellular metabolic and epigenetic states.

Ulanovskaya OA, Zuhl AM, Cravatt BF. NNMT promotes epigenetic remodeling in cancer by creating a metabolic methylation sink. Nat Chem Biol 2013 Mar 3 [Epub ahead of print].

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