Nicotinamide N-Methyltransferase in Acquisition of Stem CellProperties and Therapy Resistance in Cancer

The activity of nicotinamide N-methyltransferase (NNMT) is tightly linked to the mainte-nance of the nicotinamide adenine dinucleotide (NAD+) level. This enzyme catalyzes methylationof nicotinamide (NAM) into methyl nicotinamide (MNAM), which is either excreted or further me-tabolized to N1-methyl-2-pyridone-5-carboxamide (2-PY) and H2O2. Enzymatic activity of NNMTis important for the prevention of NAM-mediated inhibition of NAD+-consuming enzymes poly–adenosine -diphosphate (ADP), ribose polymerases (PARPs), and sirtuins (SIRTs). Inappropriatelyhigh expression and activity of NNMT, commonly present in various types of cancer, has the potentialto disrupt NAD+homeostasis and cellular methylation potential. Largely overlooked, in the contextof cancer, is the inhibitory effect of 2-PY on PARP-1 activity, which abrogates NNMT’s positive effecton cellular NAD+flux by stalling liberation of NAM and reducing NAD+synthesis in the salvagepathway. This review describes, and discusses, the mechanisms by which NNMT promotes NAD+depletion and epigenetic reprogramming, leading to the development of metabolic plasticity, evasionof a major tumor suppressive process of cellular senescence, and acquisition of stem cell properties.All these phenomena are related to therapy resistance and worse clinical outcome