Complex roles of nicotinamide N-methyltransferase in cancer progression

Abstract

Nicotinamide N-methyltransferase (NNMT) is an intracellular methyltransferase, catalyzing the N-methylation of nicotinamide (NAM) to form 1-methylnicotinamide (1-MNAM), in which S-adenosyl-l-methionine (SAM) is the methyl donor. High expression of NNMT can alter cellular NAM and SAM levels, which in turn, affects nicotinamide adenine dinucleotide (NAD+)-dependent redox reactions and signaling pathways, and remodels cellular epigenetic states. Studies have revealed that NNMT plays critical roles in the occurrence and development of various cancers, and analysis of NNMT expression levels in different cancers from The Cancer Genome Atlas (TCGA) dataset indicated that NNMT might be a potential biomarker and therapeutic target for tumor diagnosis and treatment. This review provides a comprehensive understanding of recent advances on NNMT functions in different tumors and deciphers the complex roles of NNMT in cancer progression.

Nicotinamide N-Methyltransferase Remodeled Cell Metabolism and Aggravated Proinflammatory Responses by Activating STAT3/IL1β/PGE2 Pathway

“…It has been shown that NNMT mRNA and protein are both highly expressed in various cancers and NNMT is considered as a potential biomarker and therapeutic target. 37 , 38 A few studies indicated that NNMT was more sensitive than carcinoembryonic antigen (CEA) for diagnosis of lung adenocarcinoma and colorectal cancer (CRC), and combined testing of NNMT and CEA in serum can improve the diagnosis accuracy. 11 , 12 , 39 , 40 The present study explored the underlying mechanisms of NNMT on cell metabolism and inflammatory responses by performing proteomics, secretomics, and metabolomics.…”

Nicotinamide N-Methyltransferase as Promising Tool for Management of Gastrointestinal Neoplasms

“…Due to NNMT intervention to a crucial and basically irreversible catabolic reaction of NAM, enzyme activity greatly influences the regulation of intracellular levels of NAM, whose fate is represented by urinary excretion upon N -methylation. NAM is the amide derivative of nicotinic acid (NA) [ 35 ]. In addition to the bioactive compound of vitamin B3, NAM is also a basic precursor of nicotinamide adenine dinucleotide (NAD + ), a pyridine nucleotide coenzyme participating in redox reactions featuring metabolism [ 36 ] and other processes, such as gene expression regulation at transcriptional level and mechanisms of DNA repair in response to structural damage [ 37 ].…”

“…In addition to the bioactive compound of vitamin B3, NAM is also a basic precursor of nicotinamide adenine dinucleotide (NAD + ), a pyridine nucleotide coenzyme participating in redox reactions featuring metabolism [ 36 ] and other processes, such as gene expression regulation at transcriptional level and mechanisms of DNA repair in response to structural damage [ 37 ]. Since NAM can no longer be used as an NAD + precursor substrate after N -methylation, NNMT activity also plays a fundamental role in regulating the equilibrium between NAD + biosynthesis and breakdown, thus indirectly affecting a wide range of intracellular events [ 35 ].…”

“…In this site, the enzyme is grouped among those participating in reactions featuring phase II metabolism and is described to be involved in the xenobiotic biotransformation and detoxification [ 30 , 31 , 32 ]. In hepatocytes, NNMT contributes to NAM homeostasis, together with other NAM-consuming enzymes, namely nicotinamide phosphoribosyltransferase (NAMPT) and Cytochrome P450 2E1 (CYP2E1); the latter is able to switch the catabolic fate of vitamin B3 towards N-oxidation rather than N -methylation, converting NAM into nicotinamide N -oxide (NAM N -oxide) [ 35 , 39 ] ( Figure 2 ).…”

Potent Uncompetitive Inhibitors of Nicotinamide N-Methyltransferase (NNMT) as In Vivo Chemical Probes

“…Structures that mimic the N-methyl of 1-MNA (6�8) are also inactive. Single methoxy substitutions at the four-(9, nicotinamide numbering) or two- (10) positions lead to inactivity. Installation of a methylamine at the four-position produces a compound (11) with limited activity.…”