Nicotinamide N-Methyltransferase in Head and Neck Tumors: A Comprehensive Review

Togni, Lucrezia; Mascitti, Marco; Campagna, Roberto; Pozzi, Valentina; Salvolini, Eleonora; Offidani, Annamaria; Santarelli, Andrea; Emanuelli, Monica

doi:10.3390/biom11111594

Cited by 23 publications

(22 citation statements)

References 48 publications

(95 reference statements)

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“…Our research revealed that NNMT expression was significantly variable in 24 types of tumors and paracancerous tissues, and up-regulated in nine types of malignancies, which was consistent with the immunohistochemical analysis of protein levels. The results of PAAD (Xu et al, 2016), STAD (Chen et al, 2016), KIRC (Reustle et al, 2022), GBM (Palanichamy et al, 2017), HNSC (Togni et al, 2021) and COAD (Ogawa et al, 2022) were similar to previous studies. However, the results suggested that there was a relatively high level of NNMT expression in the normal tissues of 15 distinct types of tumors, which may be a result of the vast variation in metabolic status between tumor types (Park et al, 2020;Hanahan, 2022).…”

Section: Figure 14supporting

confidence: 89%

Systematic pan-cancer analysis of the nicotinamide n-methyltransferase in human cancer

Cao

Wu²,

Deng³

et al. 2022

Front. Genet.

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In several tumors, Nicotinamide N-Methyltransferase (NNMT) was identified as a bridge between methylation metabolism and tumorigenesis and was associated with a poor prognosis. This research aims is to study the prognostic value of NNMT in cancer, its relationship with DNA methylation, and the immune microenvironment. On the basis of the Cancer Genome Atlas and the Cancer Cell Line Encyclopedia, Genotype Tissue-Expression, cBioPortal, Cellminer, Gene Expression Profiling Interactive Analysis, Human Protein Atlas and Clinical Proteomic Tumor Analysis Consortium, we used a series of bioinformatics strategies to investigate the potential carcinogenicity of NNMT, including the relationship between NNMT expression and prognosis, tumor mutational burden, microsatellite instability, and sensitivity analysis of anticancer drugs. The GeneMANIA, STRING, and BioGRID databases were examined for protein-protein interactions, and Gene Ontology and the Kyoto Encyclopedia of Genes were used to infer the signal pathway. The results indicated that NNMT was significantly expressed in several tumor tissues compared to the matching non-tumor tissues. Increased NNMT expression was linked to reduced OS, DSS, and DFI. In addition, there was a link between NNMT expression and TMB and MSI in 18 cancer types, and between NNMT expression and DNA methylation in 23 cancer types. Further study of NNMT gene alteration data revealed that deletion was the most prevalent form of NNMT mutation, and that there was a significant negative association between NNMT expression and mismatch repair genes. In addition, there was a strong positive connection between NNMT and immune infiltration in 28 types of tumors, and the immune cells that infiltrated the tumors displayed a characteristic NNMT pattern. According to the enrichment study, cell migration, cell motility, and cell adhesion were highly enriched in biological processes, and NNMT may be associated with the PI3K-Akt signaling pathway. By downregulating gene methylation or impacting the immunological microenvironment widely, NNMT may drive carcinogenesis and cause a poor prognosis. Our research showed that NNMT could be used as a biomarker of tumor immune infiltration and poor prognosis, thus providing a unique strategy for cancer therapy.

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Section: Figure 14supporting

confidence: 89%

Systematic pan-cancer analysis of the nicotinamide n-methyltransferase in human cancer

Cao

Wu²,

Deng³

et al. 2022

Front. Genet.

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“…Several metabolites indeed represent cofactors, substrates or competitive inhibitors of epigenetic enzymes. For example, mutations in isocitrate dehydrogenase (IDH) and overexpression of nicotinamide N-methyltransferase (NNMT) enzymes occur in cancers, including HNSCC, promoting cancer progression and chemoresistance, and induce alterations in DNA and histone methylation profiles [ 31 , 32 , 33 , 34 , 35 , 36 ].…”

Section: Epigenetics In Cancermentioning

confidence: 99%

High Risk-Human Papillomavirus in HNSCC: Present and Future Challenges for Epigenetic Therapies

Ghiani

Chiocca

2022

IJMS

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Head and Neck Squamous Cell Carcinoma (HNSCC) is a highly heterogeneous group of tumors characterized by an incidence of 650,000 new cases and 350,000 deaths per year worldwide and a male to female ratio of 3:1. The main risk factors are alcohol and tobacco consumption and Human Papillomavirus (HPV) infections. HNSCC cases are divided into two subgroups, the HPV-negative (HPV−) and the HPV-positive (HPV+) which have different clinicopathological and molecular profiles. However, patients are still treated with the same therapeutic regimens. It is thus of utmost importance to characterize the molecular mechanisms underlying these differences to find new biomarkers and novel therapeutic targets towards personalized therapies. Epigenetic alterations are a hallmark of cancer and can be exploited as both promising biomarkers and potential new targets. E6 and E7 HPV oncoviral proteins besides targeting p53 and pRb, impair the expression and the activity of several epigenetic regulators. While alterations in DNA methylation patterns have been well described in HPV+ and HPV− HNSCC, accurate histone post-translational modifications (hPTMs) characterization is still missing. Herein, we aim to provide an updated overview on the impact of HPV on the hPTMs landscape in HNSCC. Moreover, we will also discuss the sex and gender bias in HNSCC and how the epigenetic machinery could be involved in this process, and the importance of taking into account sex and/or gender also in this field.

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“…The physiological role of NNMT is to utilize S-adenosyl-L-methionine (SAM) to transfer methyl to nicotinamide (NAM), producing 1-methylnicotinamide (1MNA) and releasing S-adenosyl-L-homocysteine (SAH) [ 12 , 13 ]. Currently, the analysis of proteomic data has revealed that NNMT is expressed in various cancer types, including breast cancer [ 14 ], bladder cancer [ 15 ], gastric cancer [ 12 , 16 ], liver cancer [ 12 ], colorectal cancer [ 17 ], ovarian cancer [ 18 ], oral squamous cell carcinoma [ 19 ], and skin cancer [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Overexpression of NNMT in Glioma Aggravates Tumor Cell Progression: An Emerging Therapeutic Target

Sun

Zou

Cai

et al. 2022

Cancers

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Purpose: Increasing evidence has revealed that nicotinamide N-methyltransferase (NNMT) is a key factor influencing the prognosis of tumors. The present study aimed to investigate the role of NNMT in glioma and to elucidate the associated functional mechanisms. Methods: Clinical samples were analyzed by immunohistochemical staining and Western blotting to evaluate NNMT expression in glioma and normal brain tissues. The correlation between NNMT expression and glioma was analyzed using the Cancer Genome Atlas (TCGA) database. Additionally, NNMT was knocked down in two types of glioma cells, U87 and U251, to evaluate the invasive ability of these cells. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate NNMT knockdown in the cells. Furthermore, ELISA was used to determine the balance between nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide hydrogen (NAD/NADH ratio), which verified the altered methylation patterns in the cells. The glioma xenograft mouse models were used to verify the regulatory role of NNMT, GAP43, and SIRT1. Results: Analysis based on our clinical glioma samples and TCGA database revealed that overexpression of NNMT was associated with poor prognosis of patients. Knockdown of NNMT reduced the invasive ability of glioma cells, and downregulation of its downstream protein GAP43 occurred due to altered cellular methylation caused by NNMT overexpression. Gene Set Enrichment Analysis confirmed that NNMT modulated the NAD-related signaling pathway and showed a negative association between NNMT and SIRT1. Moreover, the regulatory roles of NNMT, GAP43, and SIRT1 were confirmed in glioma xenograft mouse models. Conclusion: Overexpression of NNMT causes abnormal DNA methylation through regulation of the NAD/NADH ratio, which in turn leads to the downregulation of GAP43 and SIRT1, eventually altering the biological behavior of tumor cells.

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Nicotinamide N-Methyltransferase in Head and Neck Tumors: A Comprehensive Review

Cited by 23 publications

References 48 publications

Systematic pan-cancer analysis of the nicotinamide n-methyltransferase in human cancer

Systematic pan-cancer analysis of the nicotinamide n-methyltransferase in human cancer

High Risk-Human Papillomavirus in HNSCC: Present and Future Challenges for Epigenetic Therapies

Overexpression of NNMT in Glioma Aggravates Tumor Cell Progression: An Emerging Therapeutic Target

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