Beyond Nicotinamide Metabolism: Potential Role of Nicotinamide N-Methyltransferase as a Biomarker in Skin Cancers

Abstract

Skin cancers (SC) collectively represent the most common type of malignancy in white populations. SC includes two main forms: malignant melanoma and non-melanoma skin cancer (NMSC). NMSC includes different subtypes, namely, basal cell carcinoma (BCC), squamous cell carcinoma (SCC), Merkel cell carcinoma (MCC), and keratoacanthoma (KA), together with the two pre-neoplastic conditions Bowen disease (BD) and actinic keratosis (AK). Both malignant melanoma and NMSC are showing an increasing incidence rate worldwide, thus representing an important challenge for health care systems, also because, with some exceptions, SC are generally characterized by an aggressive behavior and are often diagnosed late. Thus, identifying new biomarkers suitable for diagnosis, as well as for prognosis and targeted therapy is mandatory. Nicotinamide N-methyltransferase (NNMT) is an enzyme that is emerging as a crucial player in the progression of several malignancies, while its substrate, nicotinamide, is known to exert chemopreventive effects. Since there is increasing evidence regarding the involvement of this enzyme in the malignant behavior of SC, the current review aims to summarize the state of the art as concerns NNMT role in SC and to support future studies focused on exploring the diagnostic and prognostic potential of NNMT in skin malignancies and its suitability for targeted therapy.

Molecular Mechanisms of Cutaneous Squamous Cell Carcinoma

“…Both UVB and UVA radiation promote skin cancer by altering keratinocyte signaling, inducing oxidative stress, and producing DNA mutations [ 22 ]. UV exposure leads to ATP consumption due to the activation of DNA repair systems, which when overactivated (e.g., PARPs) is detrimental for the cell [ 23 ] (PMID: 34638427). UVB radiation possesses sufficient photonic energy to promote structural rearrangements (DNA damage) resulting in cyclobutane pyrimidine dimers (CPD) or (6-4) photoproducts [ 23 , 24 ].…”

“…UV exposure leads to ATP consumption due to the activation of DNA repair systems, which when overactivated (e.g., PARPs) is detrimental for the cell [ 23 ] (PMID: 34638427). UVB radiation possesses sufficient photonic energy to promote structural rearrangements (DNA damage) resulting in cyclobutane pyrimidine dimers (CPD) or (6-4) photoproducts [ 23 , 24 ]. If the damaged DNA strand is not repaired prior to replication, the daughter strand acquires the change in base (e.g., C ≥ T) and a mutation has occurred [ 25 ].…”

Sulforaphane and Its Bifunctional Analogs: Synthesis and Biological Activity

“…In phase II metabolism of carcinogens, a particular role is played by glutathione S-transferase (GST), NAD(P)H: quinone oxidoreductase (NQO1), UDP-glucuronyltransferase (UGT), quinone reductase (QR), and nicotinamide N -methyltransferase [ 103 , 104 ], enzymes responsible for increase the solubility of xenobiotics in water and facilitate their excretion [ 105 ]. In vitro studies on the HepG2 human hepatocyte line showed that the use of SFN ( 24 ) caused an increase in the concentration of mRNA UGT 1A1 and GST A1 [ 106 ], and an increase in the activity of NQO1 [ 107 ], accompanied by bilirubin glucuronidation [ 108 ].…”

Heterogeneity in Melanoma

“…Subsequent data revealed that EBF3 promoter methylation causes elevated EBF3 expression, which leads to metastatic characteristics in melanoma cells. Aberrant expression of methyltransferases in melanoma has also been proposed as a mechanism of malignant progression [ 32 ]. More detailed studies have subsequently been conducted to understand the phylogenetic relationship between the primary tumour and metastases.…”