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

• Published in: International journal of molecular sciences 2021-05, Vol.22 (11), p.5681
• Main Authors: Novak Kujundžić, Renata, Prpić, Marin, Đaković, Nikola, Dabelić, Nina, Tomljanović, Marko, Mojzeš, Anamarija, Fröbe, Ana, Trošelj, Koraljka Gall
• Format: Article
• Language: English
• Subjects: aldehyde oxidase; cancer; epigenetic reprogramming; nicotinamide adenine dinucleotide; nicotinamide N-methyltransferase; Review; senescence
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22115681

The activity of nicotinamide N-methyltransferase (NNMT) is tightly linked to the maintenance of the nicotinamide adenine dinucleotide (NAD+) level. This enzyme catalyzes methylation of nicotinamide (NAM) into methyl nicotinamide (MNAM), which is either excreted or further metabolized to N1-methyl-2-pyridone-5-carboxamide (2-PY) and H2O2. Enzymatic activity of NNMT is important for the prevention of NAM-mediated inhibition of NAD+-consuming enzymes poly–adenosine -diphosphate (ADP), ribose polymerases (PARPs), and sirtuins (SIRTs). Inappropriately high expression and activity of NNMT, commonly present in various types of cancer, has the potential to disrupt NAD+ homeostasis and cellular methylation potential. Largely overlooked, in the context of cancer, is the inhibitory effect of 2-PY on PARP-1 activity, which abrogates NNMT’s positive effect on cellular NAD+ flux by stalling liberation of NAM and reducing NAD+ synthesis in the salvage pathway. This review describes, and discusses, the mechanisms by which NNMT promotes NAD+ depletion and epigenetic reprogramming, leading to the development of metabolic plasticity, evasion of 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 outcomes.