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

Novak Kujundžić, Renata; Prpić, Marin; Ðaković, Nikola; Dabelić, Nina; Tomljanović, Marko; Mojzeš, Anamarija; Fröbe, Ana; Gall Trošelj, Koraljka (2021) Nicotinamide N-Methyltransferase in Acquisition of Stem CellProperties and Therapy Resistance in Cancer. International journal of molecular sciences, 22 . ISSN 1422-0067

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Abstract

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 outcomes

Item Type: Article
Uncontrolled Keywords: nicotinamide N-methyltransferase ; nicotinamide adenine dinucleotide ; aldehyde oxidase ; cancer ; epigenetic reprogramming ; senescence ; stem cell properties ; therapy resistance
Subjects: INTERDISCIPLINARY AREAS OF KNOWLEDGE > Biotechnology in Biomedicine (natural science, biomedicine and healthcare, bioethics area
Divisions: Division of Molecular Medicine
Depositing User: Renata Novak Kujundžić
Date Deposited: 03 Aug 2021 09:56
Last Modified: 03 Aug 2021 10:11
URI: http://fulir.irb.hr/id/eprint/6501
DOI: 10.3390/ijms22115681

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