The Utility of Nicotinamide N-Methyltransferase as a Potential Biomarker to Predict the Oncological Outcomes for Urological Cancers: An Update

Abstract

Nicotinamide N-methyltransferase (NNMT) catalyzes the N-methylation reaction of nicotinamide, using S-adenosyl-L-methionine as the methyl donor. Enzyme overexpression has been described in many non-neoplastic diseases, as well as in a wide range of solid malignancies. This review aims to report and discuss evidence available in scientific literature, dealing with NNMT expression and the potential involvement in main urologic neoplasms, namely, renal, bladder and prostate cancers. Data illustrated in the cited studies clearly demonstrated NNMT upregulation (pathological vs. normal tissue) in association with these aforementioned tumors. In addition to this, enzyme levels were also found to correlate with key prognostic parameters and patient survival. Interestingly, NNMT overexpression also emerged in peripheral body fluids, such as blood and urine, thus leading to candidate the enzyme as promising biomarker for the early and non-invasive detection of these cancers. Examined results undoubtedly showed NNMT as having the capacity to promote cell proliferation, migration and invasiveness, as well as its potential participation in fundamental events highlighting cancer progression, metastasis and resistance to chemo- and radiotherapy. In the light of this evidence, it is reasonable to attribute to NNMT a promising role as a potential biomarker for the diagnosis and prognosis of urologic neoplasms, as well as a molecular target for effective anti-cancer treatment.

Keywords: bladder cancer; molecular target; nicotinamide N-methyltransferase; prostate cancer; renal cell carcinoma; tumor biomarker.

Figure 1

Nicotinamide (NA) catabolism through N-methylation and N-oxidation. NA is methylated by nicotinamide N-methyltransferase (NNMT), using the universal methyl donor S-adenosyl-L-methionine (SAM) that is converted to S-adenosyl-L-homocysteine (SAH). The methylated product N1-methylnicotinamide (MNA) can be further oxidized into N1-methyl-2-pyridone-5-carboxamide (2-Py), or N1-methyl-4-pyridone-3-carboxamide (4-Py), by aldehyde oxidase (AO). NA can be oxidized to nicotinamide N-oxide (NA N-oxide) by CYP2E1 enzyme. N-methylated and N-oxidized metabolites are excreted through urine.

Figure 2

Nicotinamide N-methyltransferae (NNMT) involvement in urological tumors. Enzyme expression (tumor vs. control tissue) and its role played in cellular phenotype were explored in main urinary tract neoplasms, namely renal cell carcinoma (RCC), bladder cancer (BC) and prostate cancer (PCa).