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.
Highlights
Introduction published maps and institutional affilThe enzyme nicotinamide N-methyltransferase (NNMT, EC 2.1.1.1) catalyzes the transfer of the methyl group from the S-adenosyl-L-methionine (SAM) universal donor to nicotinamide (NA) to form N1-methylnicotinamide (MNA) and S-adenosyl-L-homocysteine (SAH) [1,2,3]
NA treatment significantly reduced sirtuin 1 (SIRT1) expression and cell migration, both in PC-3 cells overexpressing Nicotinamide N-methyltransferase (NNMT) and controls, indicating that the enzyme capacity to promote PC-3 cell malignancy is mediated by SIRT1 [112,113]
To the best of our knowledge, this is the first review reporting the concerns regarding the role played by NNMT in urological tumors, focusing on enzyme expression levels in tissues and body fluids, as well as its involvement in molecular and cellular events proin tissues and body fluids, as well as its involvement in molecular and cellular events moting malignant transformation
Summary
Renal cell carcinoma (RCC) was the first to be examined in regard to potential NNMT involvement, in which enzyme overexpression was described. Differential gene expression measurements, performed by Real-Time PCR, Western blot, and catalytic activity assay, demonstrated that NNMT levels significantly increase in tumors compared with normal kidney samples of patients affected with ccRCC. We recently reported data from Real-Time PCR analyses, performed on paired ccRCC and controlled tissue samples, of molecules potentially involved in the modulation of NNMT expression at the transcriptional level. The obtained results clearly demonstrated that, among these transcriptional regulators, TGF-β1 only displayed a significant upregulation in tumor compared with normal tissue samples of ccRCC patients [97]. Further analyses demonstrated that NNMT knockdown was associated with decreased levels of phosphorylated c-Jun, whose accumulation is responsible for G0/G1 cell cycle arrest This evidence seems to suggest a potential involvement of NNMT in molecular events connected with the antiproliferative and cell cycle-regulating effects induced by. Caki-1 cell treatment with a methanesulfonamide analogue of cryptopleurine [99]
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