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 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.

Nicotinamide metabolism regulates glioblastoma stem cell maintenance

“…The reaction driven by NNMT is irreversible, and 1-MNA, its enzymatic product, is secreted into the extracellular environment, resulting in a futile cycle of SAM and NAM consumption. Our observations are concordant with a recent report that NNMT impairs macromolecule methylation in cancer cells by consuming methyl groups from its substrates NAM and SAM (50). Therefore, NNMT-expressing cancer cells displayed altered epigenetic states with hypomethylated histones and other proteins.…”

“…The NNMT-based observations suggest a new therapeutic model for malignant GBM treatment due to multiple factors: i) mesenchymal GBMs have smaller pools of methyl donors due to elevated NNMT expression; ii) within mesenchymal tumors, GSCs display elevated levels of NNMT and NAD + , with reduced DNMT expression and DNA hypomethylation relative to DTCs; and iii) within GBMs, regions of necrosis have elevated NNMT levels, reduced methionine availability, and lower DNMT expression, leading to DNA hypomethylation ( Figure 11). This suggested mechanism is supported by the recent report showing that NNMT expression promotes histone hypomethylation by consuming SAM and methionine (50). In addition, intracellular SAM levels are maintained by methionine, a precursor of SAM, in a stem cell environment (51).…”

“…In contrast to NAMPT, NNMT is not part of the NAM salvage pathway and more directly depletes the methyl donor, SAM, which is reflected in its role in induction of DNA hypomethylation. NNMT methylates NAM to produce 1-MNA, thereby consuming SAM as a critical methyl source and increasing SAH (50,51). In human studies and animal models of oxidative stress, 1-MNA has been suggested to increase oxidative stress to promote antiinflammatory M2 polarization of macrophages, reduced proliferative exhaustion, and lifespan extension (70)(71)(72)(73).…”

“…Based on the biochemical activities of NNMT to convert SAM to SAH and NAM to 1-MNA, coupled with gene expression changes between GBMs and normal brain ( Figure 3K), we created a predictive model of the metabolic status of NAD + , methionine, and homocysteine in GSCs ( Figure 3L). NNMT-expressing tumor cells reduce methylation potential by consuming SAM as a methyl donor (50). Methionine and homocysteine metabolism regulate pluripotent stem cell maintenance and differentiation in their roles as methyl donors and metabolic regulators (51).…”

Inflammation and Pyroptosis Mediate Muscle Expansion in an Interleukin-1β (IL-1β)-dependent Manner

“…Nicotinamide can down-regulate DNA methylation and reduce the chronic inflammatory phenotype through the inhibition of methionine metabolism (29,30). In mice we found CPX-induced bladder inflammation promoted a doubling of global DNA methylation as measured by 5meC detrusor localization (Fig.…”