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1
Thomas, Martin G., Davide Sartini, Monica Emanuelli, Matthijs J. van Haren, Nathaniel I. Martin, David M. Mountford, David J. Barlow, et al. "Nicotinamide N-methyltransferase catalyses the N-methylation of the endogenous β-carboline norharman: evidence for a novel detoxification pathway." Biochemical Journal 473, no. 19 (September 27, 2016): 3253–67. http://dx.doi.org/10.1042/bcj20160219.
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Nicotinamide N-methyltransferase (NNMT) is responsible for the N-methylation of nicotinamide to 1-methylnicotinamide. Our recent studies have demonstrated that NNMT regulates cellular processes fundamental to the correct functioning and survival of the cell. It has been proposed that NNMT may possess β-carboline (BC) N-methyltransferase activity, endogenously and exogenously produced pyridine-containing compounds which, when N-methylated, are potent inhibitors of Complex I and have been proposed to have a role in the pathogenesis of Parkinson's disease. We have investigated the ability of recombinant NNMT to N-methylate norharman (NH) to 2-N-methylnorharman (MeNH). In addition, we have investigated the toxicity of the BC NH, its precursor 1,2,3,4-tetrahydronorharman (THNH) and its N-methylated metabolite MeNH, using our in vitro SH-SY5Y NNMT expression model. Recombinant NNMT demonstrated NH 2N-methyltransferase activity, with a Km of 90 ± 20 µM, a kcat of 3 × 10−4 ± 2 × 10−5 s−1 and a specificity constant (kcat/Km) of 3 ± 1 s−1 M−1. THNH was the least toxic of all three compounds investigated, whereas NH demonstrated the greatest, with no difference observed in terms of cell viability and cell death between NNMT-expressing and non-expressing cells. In NNMT-expressing cells, MeNH increased cell viability and cellular ATP concentration in a dose-dependent manner after 72 and 120 h incubation, an effect that was not observed after 24 h incubation or in non-NNNT-expressing cells at any time point. Taken together, these results suggest that NNMT may be a detoxification pathway for BCs such as NH.
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Yu, Tao, Yong-Tao Wang, Pan Chen, Yu-Hua Li, Yi-Xin Chen, Hang Zeng, Ai-Ming Yu, Min Huang, and Hui-Chang Bi. "Effects of Nicotinamide N-Methyltransferase on PANC-1 Cells Proliferation, Metastatic Potential and Survival Under Metabolic Stress." Cellular Physiology and Biochemistry 35, no. 2 (2015): 710–21. http://dx.doi.org/10.1159/000369731.
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Background: Aberrant expression of Nicotinamide N-methyltransferase (NNMT) has been reported in pancreatic cancer. However, the role of NNMT in pancreatic cancer development remains elusive. Therefore, the present study was to investigate the impact of NNMT on pancreatic cancer cell proliferation, metastatic potential and survival under metabolic stress. Methods: Pancreatic cancer cell line PANC-1 was transfected with NNMT expression plasmid or small interfering RNA of NNMT to overexpress or knockdown intracellular NNMT expression, respectively. Rate of cell proliferation was monitored. Transwell migration and matrigel invasion assays were conducted to assess cell migration and invasion capacity. Resistance to glucose deprivation, sensitivity to glycolytic inhibition, mitochondrial inhibtion and resistance to rapamycin were examined to evaluate cell survival under metabolic stress. Results: NNMT silencing markedly reduced cell proliferation, whereas NNMT overexpression promoted cell growth moderately. Knocking down NNMT also significantly suppressed the migration and invasion capacities of PANC-1 cells. Conversely, NNMT upregulation enhanced cell migration and invasion capacities. In addition, NNMT knockdown cells were much less resistant to glucose deprivation and rapamycin as well as glycolytic inhibitor 2-deoxyglucose whereas NNMT-expressing cells showed opposite effects although the effects were not so striking. Conclusions: These data sugguest that NNMT plays an important role in PANC-1 cell proliferation, metastatic potential and survival under metabolic stress.
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Liu, Wenxiu, Meng Zhu, Xiaoming Li, Limian Er, and Shengmian Li. "NNMT Is an Immune-Related Prognostic Biomarker That Modulates the Tumor Microenvironment in Pan-Cancer." Disease Markers 2023 (February 9, 2023): 1–17. http://dx.doi.org/10.1155/2023/9226712.
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Emerging evidence has revealed the significant roles of nicotinamide n-methyltransferase (NNMT) in cancer initiation, development, and progression; however, a pan-cancer analysis of NNMT has not been conducted. In this study, we first thoroughly investigated the expression and prognostic significance of NNMT and the relationship between NNMT and the tumor microenvironment using bioinformatic analysis. NNMT was significantly increased and associated with poor prognosis in many common cancers. NNMT expression correlated with the infiltration levels of cancer-associated fibroblasts and macrophages in pan-cancer. Function enrichment analysis discovered that NNMT related to cancer-promoting and immune pathways in various common cancers, such as colon adenocarcinoma, head and neck squamous cell carcinoma, ovarian serous cystadenocarcinoma, and stomach adenocarcinoma. NNMT expression was positively correlated with tumor-associated macrophages (TAMs), especially M2-like TAMs. The results suggest that NNMT might be a new biomarker for immune infiltration and poor prognosis in cancers, providing new direction on therapeutics of cancers.
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Sun, Wei, Yongxiang Zou, Zheng Cai, Jinxiang Huang, Xinjie Hong, Qiang Liang, and Weilin Jin. "Overexpression of NNMT in Glioma Aggravates Tumor Cell Progression: An Emerging Therapeutic Target." Cancers 14, no. 14 (July 21, 2022): 3538. http://dx.doi.org/10.3390/cancers14143538.
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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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Parsons, Richard B., Shylesh Aravindan, Anusha Kadampeswaran, Emily A. Evans, Kanwaljeet K. Sandhu, Elizabeth R. Levy, Martin G. Thomas, Brian M. Austen, and David B. Ramsden. "The expression of nicotinamide N-methyltransferase increases ATP synthesis and protects SH-SY5Y neuroblastoma cells against the toxicity of Complex I inhibitors." Biochemical Journal 436, no. 1 (April 27, 2011): 145–55. http://dx.doi.org/10.1042/bj20101685.
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NNMT (nicotinamide N-methyltransferase, E.C. 2.1.1.1) catalyses the N-methylation of nicotinamide to 1-methylnicotinamide. NNMT expression is significantly elevated in a number of cancers, and we have previously demonstrated that NNMT expression is significantly increased in the brains of patients who have died of Parkinson's disease. To investigate the cellular effects of NNMT overexpression, we overexpressed NNMT in the SH-SY5Y cell line, a tumour-derived human dopaminergic neuroblastoma cell line with no endogenous expression of NNMT. NNMT expression significantly decreased SH-SY5Y cell death, which correlated with increased intracellular ATP content, ATP/ADP ratio and Complex I activity, and a reduction in the degradation of the NDUFS3 [NADH dehydrogenase (ubiquinone) iron–sulfur protein 3] subunit of Complex I. These effects were replicated by incubation of SH-SY5Y cells with 1-methylnicotinamide, suggesting that 1-methylnicotinamide mediates the cellular effects of NNMT. Both NNMT expression and 1-methylnicotinamide protected SH-SY5Y cells from the toxicity of the Complex I inhibitors MPP+ (1-methyl-4-phenylpyridinium ion) and rotenone by reversing their effects upon ATP synthesis, the ATP/ADP ratio, Complex I activity and the NDUFS3 subunit. The results of the present study raise the possibility that the increase in NNMT expression that we observed in vivo may be a stress response of the cell to the underlying pathogenic process. Furthermore, the results of the present study also raise the possibility of using inhibitors of NNMT for the treatment of cancer.
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Zhang, Weixian, Yue Jing, Shuai Wang, Yan Wu, Yawei Sun, Jia Zhuang, Xiaofeng Huang, et al. "Identification of Biological Functions and Prognostic Value of NNMT in Oral Squamous Cell Carcinoma." Biomolecules 12, no. 10 (October 15, 2022): 1487. http://dx.doi.org/10.3390/biom12101487.
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Background: Nicotinamide N-methyltransferase (NNMT) is a metabolic enzyme that catalyzes the methylation of nicotinamide (NAM) to generate 1-methyl nicotinamide (MNAM). Although previous studies have shown that NNMT is frequently dysregulated to promote the onset and progression of many malignancies, its expression profile, prognostic value and function in oral squamous cell carcinoma (OSCC) are still unknown. Methods: We used untargeted metabolomics based on mass spectrometry to analyze potential metabolite differences between tumors and matched adjacent normal tissues in 40 OSCC patients. Immunohistochemistry (IHC) was used to analyze the NNMT expression profile in OSCC, and the diagnostic and prognostic values of NNMT were evaluated. Next, qPCR and Western blot were used to compare the expression of NNMT in five OSCC cell lines. Stable transfected cell lines were constructed, and functional experiments were carried out to elucidate the effects of NNMT on the proliferation and migration of OSCC cells. Finally, gene set enrichment analysis (GSEA) was performed using The Cancer Genome Atlas (TCGA) data to investigate the potential functional mechanisms of NNMT in OSCC. Results: We found that the nicotinamide metabolic pathway was abnormally activated in OSCC tumor tissues compared with normal tissues. NNMT was expressed ubiquitously in tumor cells (TCs) and fibroblast-like cells (FLCs) but was absent in tumor-infiltrating lymphocytes (TILs). OSCC patients with highly expressed NNMT in TCs had higher risk of lymph node metastasis and showed a worse pattern of invasion (POI). Moreover, patients with highly expressed NNMT were also susceptible to postoperative recurrence. Highly expressed NNMT can independently predict shorter disease-free survival and recurrence-free survival. Functionally, we demonstrated that the ectopic expression of NNMT promoted OSCC tumor cell proliferation and migration in vitro. Conversely, silencing exerted significantly opposite effects in vitro. In addition, GSEA showed that highly expressed NNMT was mainly enriched in the epithelial–mesenchymal transformation (EMT) pathway, which displayed a significant positive correlation with the six classic EMT markers. Conclusions: Our study uncovered that NNMT may be a critical regulator of EMT in OSCC and may serve as a prognostic biomarker for OSCC patients. These findings might provide novel insights for future research in NNMT-targeted OSCC metastasis and recurrence therapy.
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Parsons, Richard B., and Paul D. Facey. "Nicotinamide N-Methyltransferase: An Emerging Protagonist in Cancer Macro(r)evolution." Biomolecules 11, no. 10 (September 28, 2021): 1418. http://dx.doi.org/10.3390/biom11101418.
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Nicotinamide N-methyltransferase (NNMT) has progressed from being considered merely a Phase II metabolic enzyme to one with a central role in cell function and energy metabolism. Over the last three decades, a significant body of evidence has accumulated which clearly demonstrates a central role for NNMT in cancer survival, metastasis, and drug resistance. In this review, we discuss the evidence supporting a role for NNMT in the progression of the cancer phenotype and how it achieves this by driving the activity of pro-oncogenic NAD+-consuming enzymes. We also describe how increased NNMT activity supports the Warburg effect and how it promotes oncogenic changes in gene expression. We discuss the regulation of NNMT activity in cancer cells by both post-translational modification of the enzyme and transcription factor binding to the NNMT gene, and describe for the first time three long non-coding RNAs which may play a role in the regulation of NNMT transcription. We complete the review by discussing the development of novel anti-cancer therapeutics which target NNMT and provide insight into how NNMT-based therapies may be best employed clinically.
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Liu, Jie-Ru, Zhao-Hui Deng, Xiao-Juan Zhu, Yu-Rong Zeng, Xiang-Xiang Guan, and Jiang-Hua Li. "Roles of Nicotinamide N-Methyltransferase in Obesity and Type 2 Diabetes." BioMed Research International 2021 (July 27, 2021): 1–8. http://dx.doi.org/10.1155/2021/9924314.
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Type 2 diabetes (T2D) is thought to be a complication of metabolic syndrome caused by disorders of energy utilization and storage and characterized by insulin resistance or deficiency of insulin secretion. Though the mechanism linking obesity to the development of T2D is complex and unintelligible, it is known that abnormal lipid metabolism and adipose tissue accumulation possibly play important roles in this process. Recently, nicotinamide N-methyltransferase (NNMT) has been emerging as a new mechanism-of-action target in treating obesity and associated T2D. Evidence has shown that NNMT is associated with obesity and T2D. NNMT inhibition or NNMT knockdown significantly increases energy expenditure, reduces body weight and white adipose mass, improves insulin sensitivity, and normalizes glucose tolerance and fasting blood glucose levels. Additionally, trials of oligonucleotide therapeutics and experiments with some small-molecule NNMT inhibitors in vitro and in preclinical animal models have validated NNMT as a promising therapeutic target to prevent or treat obesity and associated T2D. However, the exact mechanisms underlying these phenomena are not yet fully understood and clinical trials targeting NNMT have not been reported until now. Therefore, more researches are necessary to reveal the acting mechanism of NNMT in obesity and T2D and to develop therapeutics targeting NNMT.
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Griffiths, Alexandra, Jun Wang, Qing Song, Iredia D. Iyamu, Lifeng Liu, Jooman Park, Yuwei Jiang, Rong Huang, and Zhenyuan Song. "Nicotinamide N-methyltransferase upregulation via the mTORC1-ATF4 pathway activation contributes to palmitate-induced lipotoxicity in hepatocytes." American Journal of Physiology-Cell Physiology 321, no. 3 (September 1, 2021): C585—C595. http://dx.doi.org/10.1152/ajpcell.00195.2021.
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Defined as the dysfunction and/or cell death caused by toxic lipids accumulation in hepatocytes, hepatic lipotoxicity plays a pathological role in nonalcoholic fatty liver disease. The cellular and molecular mechanisms underlying lipotoxicity remain to be elucidated. In this study, using AML12 cells, a nontransformed murine hepatocyte cell line, exposed to palmitate (a 16-C saturated fatty acid) as an experimental model, we investigated the role and mechanisms of nicotinamide N-methyltransferase (NNMT), a methyltransferase catalyzing nicotinamide methylation and degradation, in hepatic lipotoxicity. We initially identified activating transcription factor 4 (ATF4) as a major transcription factor for hepatic NNMT expression. Here, we demonstrated that palmitate upregulates NNMT expression via activating ATF4 in a mechanistic target of rapamycin complex 1 (mTORC1)-dependent mechanism in that mTORC1 inhibition by both Torin1 and rapamycin attenuated ATF4 activation and NNMT upregulation. We further demonstrated that the mTORC1-dependent ATF4 activation is an integral signaling event of unfolded protein response (UPR) as both ATF4 activation and NNMT upregulation by tunicamycin, a well-documented endoplasmic reticulum (ER) stress inducer, are blunted when hepatocytes were pretreated with Torin1. Importantly, our data uncovered that NNMT upregulation contributes to palmitate-induced hepatotoxicity as NNMT inhibition, via either pharmacological (NNMT inhibitors) or genetic approach (siRNA transfection), provided protection against palmitate lipotoxicity. Our further mechanistic exploration identified protein kinase A (PKA) activation to contribute, at least, partially to the protective effect of NNMT inhibition against lipotoxicity. Collectively, our data demonstrated that NNMT upregulation by the mTORC1-ATF4 pathway activation contributes to the development of lipotoxicity in hepatocytes.
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Li, Guoli, Sining Fang, Xiao Shao, Yejia Li, Qingchao Tong, Beibei Kong, Lifen Chen, et al. "Curcumin Reverses NNMT-Induced 5-Fluorouracil Resistance via Increasing ROS and Cell Cycle Arrest in Colorectal Cancer Cells." Biomolecules 11, no. 9 (August 31, 2021): 1295. http://dx.doi.org/10.3390/biom11091295.
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Nicotinamide N-methyltransferase (NNMT) plays multiple roles in improving the aggressiveness of colorectal cancer (CRC) and enhancing resistance to 5-Fluorouracil (5-FU), making it an attractive therapeutic target. Curcumin (Cur) is a promising natural compound, exhibiting multiple antitumor effects and potentiating the effect of 5-FU. The aim of the present study is to explore the effect of Cur on attenuating NNMT-induced resistance to 5-FU in CRC. A panel of CRC cell lines with different NNMT expressions are used to characterize the effect of Cur. Herein, it is observed that Cur can depress the expression of NNMT and p-STAT3 in CRC cells. Furthermore, Cur can induce inhibition of cell proliferation, G2/M phase cell cycle arrest, and reactive oxygen species (ROS) generation, especially in high-NNMT-expression CRC cell lines. Cur can also re-sensitize high-NNMT-expression CRC cells to 5-FU both in vitro and in vivo. In summary, it is proposed that Cur can reverse NNMT-induced cell proliferation and 5-FU resistance through ROS generation and cell cycle arrest. Given that Cur has long been used, we suppose that Cur is a promising anticancer drug candidate with minimal side effects for human CRC therapy and can attenuate NNMT-induced resistance to 5-FU.
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Sartini, Davide, Riccardo Seta, Valentina Pozzi, Stefano Morganti, Corrado Rubini, Antonio Zizzi, Marco Tomasetti, Lory Santarelli, and Monica Emanuelli. "Role of nicotinamide N-methyltransferase in non-small cell lung cancer: in vitro effect of shRNA-mediated gene silencing on tumourigenicity." Biological Chemistry 396, no. 3 (March 1, 2015): 225–34. http://dx.doi.org/10.1515/hsz-2014-0231.
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Abstract Lung cancer is the second most commonly diagnosed neoplasm, and represents the leading cause of tumour death worldwide. As patients are often diagnosed at a late stage, current therapeutic strategies have limited effectiveness and the prognosis remains poor. Successful treatment depends on early diagnosis and knowledge concerning molecular mechanisms underlying lung carcinogenesis. In the present study, we focused on nicotinamide N-methyltransferase (NNMT), which is overexpressed in several malignancies. First, we analysed NNMT expression in a cohort of 36 patients with non-small cell lung cancer (NSCLC) by immunohistochemistry. Subsequently, we examined NNMT expression levels in the human lung cancer cell line A549 by Real-Time PCR, Western blot and catalytic activity assay, and evaluated the effect of NNMT knockdown on cell proliferation and anchorage-independent cell growth by MTT and soft agar colony formation assays, respectively. NSCLC displayed higher NNMT expression levels compared to both tumour-adjacent and surrounding tissue. Moreover, shRNA-mediated gene silencing of NNMT led to a significant inhibition of cell proliferation and colony formation ability on soft agar. Our results show that the downregulation of NNMT significantly reduced in vitro tumorigenicity of A549 cells and suggest that NNMT could represent an interesting molecular target for lung cancer therapy.
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Huang, Rong, and Iredia Iyamu. "Abstract A024: Development of potent and selective nicotinamide N-methyltransferase inhibitors for kidney cancer." Cancer Research 83, no. 16_Supplement (August 15, 2023): A024. http://dx.doi.org/10.1158/1538-7445.kidney23-a024.
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Abstract Nicotinamide N-methyltransferase (NNMT) is a metabolic enzyme that regulates energy balance and methylation potential through the methylation of nicotinamide using S-adenosylmethionine (SAM) as the cofactor. NNMT has emerged as a novel target for both primary and metastatic ccRCC, as its high expression in ccRCC tumor tissues is linked with low survival. Meanwhile, NNMT depletion or inhibition efficiently suppresses the growth and metastasis of ccRCC in cellular and animal studies. Here, we report rational design and synthesize cell-potent and selective NNMT inhibitors with cellular IC50 values of 140 nM, representing the most cell-potent inhibitors to date. Furthermore, our NNMT inhibitors suppress renal cancer 786O and Caki-1 cell growth with a GI50 value of 9.3 and 7.3 µM, respectively. Moreover, our NNMT inhibitors reduced the migration of renal cancer cells through wound healing assay. In summary, our inhibitors would serve as valuable chemical probes to investigate the catalytical function of NNMT and evaluate the therapeutic potential of NNMT for kidney cancer. Citation Format: Rong Huang, Iredia Iyamu. Development of potent and selective nicotinamide N-methyltransferase inhibitors for kidney cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr A024.
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Wang, Wenxuan, Wenzheng Li, Ying Bu, Xuepeng Li, and Wenhui Zhu. "Nano Freezing–Thawing of Atlantic Salmon Fillets: Impact on Thermodynamic and Quality Characteristics." Foods 12, no. 15 (July 29, 2023): 2887. http://dx.doi.org/10.3390/foods12152887.
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The presence of magnetic nanoparticles (MNPs) suppresses ice nucleation and growth during freezing and thawing. In this study, the effects of MNPs-assisted cryogenic freezing integrated with MNP-combined microwave thawing (NNMT) on the thermodynamic and quality changes of salmon fillets were investigated. Results have shown that NNMT raises Tg (glass transition temperature) and Tmax (transition temperature), thus improving the storage stability of salmon fillets. MNPs-assisted freezing and thawing treatment, especially NNMT treatment, significantly improved the water holding capacity, texture, color, and other quality characteristics of salmon fillets. In addition, the lipid and protein oxidation degrees of the NNMT treatment were the lowest, while the myofibrillar protein solubility of NNMT was the highest (87.28%). This study demonstrated that NNMT has minimal impact on the freezing–thawing quality of salmon fillets, making it a more suitable option for the preservation of aquatic foods.
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Heide, Janna, Andras Piffko, Agnes J. Bilecz, Ethan A. Teich, Lisa Schweizer, Sayed R. Alhunayan, Kaiting Yang, and Ernst Lengyel. "Abstract 4462: Immunoregulatory effects of NNMT-expressing cancer-associated fibroblasts." Cancer Research 83, no. 7_Supplement (April 4, 2023): 4462. http://dx.doi.org/10.1158/1538-7445.am2023-4462.
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Abstract Nicotinamide N-methyltransferase (NNMT) is highly expressed in the stroma of several malignancies and has been shown to drive the transformation of resting fibroblasts into cancer-associated fibroblasts (CAFs) through epigenetic changes. Given that CAFs can promote immunosuppression in cancer, the aim of our study was to investigate the effect of NNMT-expressing CAFs on the tumor-immune environment. Using a co-culture system of normal fibroblasts and activated PBMCs, we found that IFN-γ produced by PBMCs upregulates NNMT expression in fibroblasts. We confirmed this mechanism in vivo in IFN-γ knockout mice and identified T cells as the main source of IFN-γ in the tumor. Gene expression and protein analysis showed that upregulation of NNMT in CAFs induces the secretion of the chemokine CXCL1, a critical chemoattractant for immunosuppressive myeloid-derived suppressor cells (MDSCs). Upregulation of NNMT induces CXCL1 secretion directly through promoter hypomethylation, and in vitro migration assays show that NNMT-expressing CAFs recruit high numbers of MDSCs. Using spectral flow cytometry, we analyzed the tumor-immune cell infiltration in whole-body NNMT-knockout mice and discovered that NNMT knockout of the stroma significantly reduced the abundance of MDSCs and increased the number of functional CD8+ T cells. Increased T cell cytotoxicity was associated with a significant reduction in tumor burden in the syngeneic ID8 ovarian and MC38 colon cancer models. These findings were confirmed after adoptive transfer of NNMT-wildtype immune cells into irradiated whole-body NNMT-knockout mice. Moreover, in scRNA-seq data of various human malignancies, we found a strong correlation between NNMT and CXCL1 expression in CAFs. In summary, our results support a model in which cancer cells induce IFN-γ secretion by T-cells, thereby upregulating NNMT expression in fibroblasts, leading to CXCL1 secretion. CXCL1 secreted by CAFs recruits MDSCs to the tumor, which in turn suppress the anti-tumor T cell response. Citation Format: Janna Heide, Andras Piffko, Agnes J. Bilecz, Ethan A. Teich, Lisa Schweizer, Sayed R. Alhunayan, Kaiting Yang, Ernst Lengyel. Immunoregulatory effects of NNMT-expressing cancer-associated fibroblasts. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4462.
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Chee, Woei-Yaw, Deniz Nesli Dolcen, Lynda Bennett, and Suzanne D. Conzen. "Abstract 3697: Modulation of Nicotinamide N-Methyl Transferase (NNMT) expression in TNBC is associated with altered cell membrane cholesterol levels." Cancer Research 83, no. 7_Supplement (April 4, 2023): 3697. http://dx.doi.org/10.1158/1538-7445.am2023-3697.
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Abstract Introduction: Cancer cells often develop a program of metabolic adaptability and epigenetic remodelling to promote gene expression changes causing cancerous cell proliferation and invasion. The metabolic-epigenetic axis as a an underlying mechanism of carcinogenesis could lead to new approaches to cancer treatment. Nicotinamide N-Methyl Transferase (NNMT) is a metabolic enzyme that catalyzes the transfer of a methyl group from S-Adenosyl methionine (SAM) to nicotinamide, thereby decreasing the overall methyl pools for RNA, histone and DNA methylation. High NNMT expression has been previously associated with a poor outcome in TNBC. Hypothesis: We hypothesized that high versus low NNMT activity and resulting oncogenic gene expression in TNBC may alter histone methylation is association with altered metabolic pathway activation. Methods: We used two TNBC cell lines models, MDA-MB 231 and SUM159, to study the association between high versus low NNMT activity and metabolic pathway activation. Surprisingly, we identified gene expression pathways suggestive of increased free cholesterol biosynthesis gene expression with low NNMT, and then used biochemical assays and filipin to measure free cholesterol in both total high and low NNMT TNBC cell lysates and relative cholesterol expression in the High vs Low NNMT cell membranes. Results: In vitro, NNMT knockdown resulted in increased cholesterol synthetic pathway enzyme expression in both TNBC cell lines. In vivo studies also showed that protein expression of cholesterol synthesis enzymes was also increased in NNMT-depleted MDA-MB 231 xenografted tumors. Interestingly, the increased cholesterol level upon NNMT depletion was mainly localized at the plasma membrane via Filipin III staining, suggesting a possible association with less cellular membrane fluidity and a decreased oncogenic phenotype. In ongoing experiments, we are evaluating whether changes in histone methylation in high vs low NNMT cells are associated with differential expression of cholesterol biosynthetic genes, and free cholesterol production. We hypothesize that NNMT might epigenetically decrease the methylation of histones regulating cholesterol production in TNBC. Citation Format: Woei-Yaw Chee, Deniz Nesli Dolcen, Lynda Bennett, Suzanne D. Conzen. Modulation of Nicotinamide N-Methyl Transferase (NNMT) expression in TNBC is associated with altered cell membrane cholesterol levels. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3697.
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Ma, Lianping, and Ming Li. "Abstract 2545: NNMT is a novel effector of EGFR driven glioblastoma malignancy." Cancer Research 83, no. 7_Supplement (April 4, 2023): 2545. http://dx.doi.org/10.1158/1538-7445.am2023-2545.
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Abstract Nicotinamide N-methyltransferase (NNMT) is a metabolic enzyme that catalyzes the conversion of methyl groups from S-adenosyl-L-methionine (SAM) to nicotinamide (NAM) to generate S-adenosine hyperblastoids (SAH) and 1-methylnicotinamide (MNA). Upregulation of NNMT has been observed in a variety of cancers, including glioblastoma. The mechanism by which NNMT is overexpressed in glioblastoma remains largely unknown. Epidermal growth factor receptor (EGFR) gene amplification or mutation is one of the most common genetic lesions in glioblastoma, and EGFRvIII is the most common mutant contributing to glioblastoma cell proliferation, invasion, therapeutic resistance, metastasis, and stemness. In this study, we show that activation of wild-type EGFR by EGF or the constitutively active mutant EGFRvIII promoted NNMT expression in established glioblastoma cell lines and glioblastoma stem-like cells via the p38 mitogen-activated protein kinase pathway. Furthermore, we identified STAT1 as a downstream transcription factor required for EGFR/EGFRvIII-induced NNMT upregulation. Knockdown of NNMT by RNA interference in glioblastoma cells significantly inhibited EGFRvIII-promoted glioblastoma cell invasion and proliferation in vitro. Targeting NNMT inhibited EGFRvIII-driven glioblastoma tumorigenicity and prolonged survival of tumor-bearing mice. Clinically, NNMT was highly expressed and positively correlated with EGFR expression in human glioblastoma tumors. Taken together, these findings establish NNMT as a previously unknown downstream target gene of EGFR/EGFRvIII expression and nominate it as a new potential therapeutic target for inhibiting EGFRvIII-driven glioblastoma. Citation Format: Lianping Ma, Ming Li. NNMT is a novel effector of EGFR driven glioblastoma malignancy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2545.
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Dang, Ling, and Yingdong Wang. "Prognostic value of nicotinamide N-methyltransferase in human cancers: Evidence from a meta-analysis and database validation." Open Medicine 17, no. 1 (January 1, 2022): 292–303. http://dx.doi.org/10.1515/med-2022-0413.
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Abstract Background Previous studies indicated that dysregulated expression of nicotinamide N-methyltransferase (NNMT) contributed to the tumor progression and predicted poor prognosis in various cancers. However, there was no exact conclusion on account of the contradictory results across studies. Methods The relevant studies up to December 7, 2020 were searched in PubMed, Web of Science, and Embase. The association between NNMT expression and prognostic outcomes was explored, including overall survival (OS), disease-free survival (DFS), and clinicopathological features. The bioinformatics database was used to validate the findings. Results Thirteen retrospective studies containing 2,591 patients with cancers were included in this analysis. High NNMT expression was significantly associated with shorter OS (hazard ratio [HR] = 2.01, 95% confidence interval [CI] = 1.42–2.86, and P < 0.01) and DFS (HR = 1.59, 95% CI = 1.23–2.05, and P < 0.01) compared to low NNMT expression in cancers. Compared to patients with low NNMT expression, patients with high NNMT expression tended to have worse tumor differentiation (P = 0.03), earlier lymph node metastasis (P = 0.01), earlier distant metastasis (P = 0.02), and more advanced clinical stage (P < 0.01). Conclusion High NNMT expression is an unfavorable factor of various cancers. NNMT is a promising indicator to predict the prognosis of various cancers and can serve as a potential therapeutic target in various cancers.
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Togni, Lucrezia, Marco Mascitti, Davide Sartini, Roberto Campagna, Valentina Pozzi, Eleonora Salvolini, Annamaria Offidani, Andrea Santarelli, and Monica Emanuelli. "Nicotinamide N-Methyltransferase in Head and Neck Tumors: A Comprehensive Review." Biomolecules 11, no. 11 (October 28, 2021): 1594. http://dx.doi.org/10.3390/biom11111594.
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The head and neck tumors (HNT) are a heterogeneous group of diseases ranging from benign to malignant lesions, with distinctive molecular and clinical behaviors. Several studies have highlighted the presence of an altered metabolic phenotype in HNT, such as the upregulation of nicotinamide N-methyltransferase (NNMT). However, its biological effects have not been completely disclosed and the role of NNMT in cancer cell metabolism remains unclear. Therefore, this comprehensive review aims to evaluate the available literature regarding the biological, diagnostic, and prognostic role of NNMT in HNT. NNMT was shown to be significantly overexpressed in all of the evaluated HNT types. Moreover, its upregulation has been correlated with cancer cell migration and adverse clinical outcomes, such as high-pathological stage, lymph node metastasis, and locoregional recurrences. However, in oral squamous cell carcinoma (OSCC) these associations are still debated, and several studies have failed to demonstrate the prognostic significance of NNMT. The shRNA-mediated gene silencing efficiently suppressed the NNMT gene expression and exhibited a clear inhibitory effect on cell proliferation, promoting the expression of apoptosis-related proteins and modulating the cell cycle. NNMT could represent a new molecular biomarker and a new target of molecular-based therapy, although further studies on larger patient cohorts are needed to explore its biological role in HNT.
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Liang, Tairong, Xiuqian Wu, Lan Wang, Tiantian Song, Peishan Wu, Yongdong Niu, and Haihua Huang. "Correlation of NNMT and DKK1 Protein Expression With Clinicopathological Characteristics and Prognosis of Breast Cancer." Clinical Medicine Insights: Oncology 17 (January 2023): 117955492311680. http://dx.doi.org/10.1177/11795549231168073.
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Background: Nicotinamide N-methyltransferase (NNMT) and Dickkopf-1 (DKK1) play an important role in the development of breast cancer, and the purpose of this study was designed to examine the clinical and prognostic significance of NNMT and DKK1 in breast cancer. Methods: The GEPIA2 database was used to evaluate the expression and survival of NNMT mRNA and DKK1 mRNA of breast cancer. Then an immunohistochemical study was carried out on 374 cases of breast tissue to identify the protein expression and significance of NNMT and DKK1. Next, the prognostic significance of DKK1 in breast cancer was explored by COX and Kaplan-Meier models. Results: Protein NNMT expression was correlated with lymph node metastasis and histological grade ( P < .05) while protein DKK1 expression was related to tumor size, pT stage, histological grade, and Ki-67 ( P < .05). Protein DKK1 was related to disease-specific survival (DSS), and low DKK1 expression indicated a poor prognosis of breast cancer patients ( P < .05). Combined expression of protein NNMT and protein DKK1 predicted different prognosis of DSS ( P < .05). Conclusions: Nicotinamide N-methyltransferase and DKK1 were linked to breast cancer malignancy and invasion. Breast cancer patients with low DKK1 expression had a worse prognosis. Oncotypes of NNMT and DKK1 expression predicted patient outcomes.
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Li, Qian, Min-Di He, Lin Mao, Xue Wang, Yu-Lin Jiang, Min Li, Yong-Hui Lu, Zheng-Ping Yu, and Zhou Zhou. "Nicotinamide N-Methyltransferase Suppression Participates in Nickel-Induced Histone H3 Lysine9 Dimethylation in BEAS-2B Cells." Cellular Physiology and Biochemistry 41, no. 5 (2017): 2016–26. http://dx.doi.org/10.1159/000475432.
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Background: Nickel compounds are well-established human carcinogens with weak mutagenic activity. Histone methylation has been proposed to play an important role in nickel-induced carcinogenesis. Nicotinamide N-methyltransferase (NNMT) decreases histone methylation in several cancer cells by altering the cellular ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH). However, the role of NNMT in nickel-induced histone methylation remains unclear. Methods: BEAS-2B cells were exposed to different concentrations of nickel chloride (NiCl2) for 72 h or 200 μM NiCl2 for different time periods. Histone H3 on lysine 9 (H3K9) mono-, di-, and trimethylation and NNMT protein levels were measured by western blot analysis. Expressions of NNMT mRNA and the H3k9me2-associated genes, mitogen-activated protein kinase 3 (MAP2K3) and dickkopf1 (DKK1), were determined by qPCR analysis. The cellular ratio of nicotinamide adenine dinucleotide (NAD+) to reduced NAD (NADH) and SAM/SAH ratio were determined. Results: Exposure of BEAS-2B cells to nickel increased H3K9 dimethylation (H3K9me2), suppressed the expressions of H3K9me2-associated genes (MAP2K3 and DKK1), and induced NNMT repression at both the protein and mRNA levels. Furthermore, over-expression of NNMT inhibited nickel-induced H3K9me2 and altered the cellular SAM/SAH ratio. Additionally, the NADH oxidant phenazine methosulfate (PMS) not only reversed the nickel-induced reduction in NAD+/NADH but also inhibited the increase in H3K9me2. Conclusions: These findings indicate that the repression of NNMT may underlie nickel-induced H3K9 dimethylation by altering the cellular SAM/SAH ratio.
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Pozzi, Valentina, Giulia Di Ruscio, Davide Sartini, Roberto Campagna, Riccardo Seta, Paola Fulvi, Alexia Vici, et al. "Clinical performance and utility of a NNMT-based urine test for bladder cancer." International Journal of Biological Markers 33, no. 1 (November 11, 2017): 94–101. http://dx.doi.org/10.5301/ijbm.5000311.
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Background: Bladder cancer (BC) represents the most common neoplasm of the urinary tract. Although cystoscopy and urine cytology represent the gold standard methods to monitor BC, both procedures have limitations. Therefore, the identification of reliable biomarkers for early and noninvasive detection of BC is urgently required. Methods: In this study, we analyzed nicotinamide N-methyltransferase (NNMT) expression in urine samples from 55 BC patients and 107 controls, using real-time polymerase chain reaction (PCR). Receiver operating characteristic (ROC) analysis was used to identify the best cutoff value to discriminate BC patients from healthy donors, and to evaluate the diagnostic accuracy of a urine-based NNMT test. Results: The results demonstrated that urinary NNMT expression was significantly (p<0.05) higher in BC patients. Moreover, a significant (p<0.05) inverse correlation was found between NNMT expression and histological grade. The ROC analysis revealed that a ΔCq of 13.3 was the best cutoff value, since it was associated with the highest combination of sensitivity and specificity. Moreover, the area under the curve (AUC) value was 0.913 (p<0.05), indicating the excellent diagnostic accuracy of a urine-based NNMT test. Conclusions: Our data indicate that NNMT is a promising biomarker that could be used to support the early and noninvasive diagnosis of BC.
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Campagna, Roberto, Valentina Pozzi, Graziana Spinelli, Davide Sartini, Giulio Milanese, Andrea Benedetto Galosi, and Monica Emanuelli. "The Utility of Nicotinamide N-Methyltransferase as a Potential Biomarker to Predict the Oncological Outcomes for Urological Cancers: An Update." Biomolecules 11, no. 8 (August 16, 2021): 1214. http://dx.doi.org/10.3390/biom11081214.
Full textAbstract:
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.
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Koppe, Tiago De Bone, Bonnie Patchen, Aaron Cheng, Manoj Bhasin, Chris D. Vulpe, Jose M. Fernandez-Real, Robert K. Schwartz, Pavlos Pissios, and Paula G. Fraenkel. "Nicotinamide N-Methyltransferase Expression Decreases in Iron Overload Exacerbating Iron-Induced Hepatotoxicity." Blood 128, no. 22 (December 2, 2016): 204. http://dx.doi.org/10.1182/blood.v128.22.204.204.
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Abstract Iron overload causes the generation of reactive oxygen species, which can lead to liver failure, particularly when it occurs in conjunction with nonalcoholic fatty liver disease (NAFLD) or viral hepatitis. Previously, we studied the effects of iron deficiency and iron overload on the hepatic transcriptional and metabolomic profile in mice. We found that iron overload induced significant changes in the expression of genes and metabolites involved in glucose and nicotinamide metabolism in both a dietary model, high iron diet, and a genetic model, hemojuvelin knockout mice. In particular, we discovered that the transcript, Nicotinamide N-methyltransferase (NNMT), was significantly downregulated in both models of iron overload. NNMT methylates nicotinamide, a form of vitamin B3, and has recently been shown to play a critical role in hepatic glucose and cholesterol metabolism by stabilizing Sirtuin 1, a nicotinamide-dependent deacetylase. For the current study, we evaluated 63 morbidly obese human subjects who gave written informed consent, validated and approved by the ethical committee of the Hospital Universitari Dr. Josep Trueta (Comitè d'Ètica d'Investigació Clínica, approval number 2009046), for the collection of liver biopsy samples and sera at the time of bariatric surgery after 8 hours of fasting. In these subjects, we found that log hepatic transcript levels of NNMT negatively correlated with measures of body iron stores, including log serum ferritin levels (R=-0.39, p=0.002) and log percent transferrin saturation (R=-0.21, p=0.02). We then performed experiments in primary hepatocytes to evaluate the interaction of iron overload and NNMT. We found that treatment with ferric ammonium citrate significantly decreased NNMT transcript levels in either primary human or mouse hepatocytes. We manipulated NNMT expression in primary mouse hepatocytes using adenoviral vectors and discovered that NNMT knockdown exacerbated iron-induced cytotoxicity and enhanced iron-induced expression of transcriptional markers of oxidative and endoplasmic reticulum stress, while NNMT overexpression protected against iron-induced cytotoxicity. In future studies, we would like to elucidate the mechanisms by which NNMT modulates hepatocyte sensitivity to iron overload. A deeper understanding of the relationship of the pathways involved in maintaining iron and energy homeostasis may reveal new therapeutic targets for patients with iron overload disorders, obesity, and NAFLD. Disclosures No relevant conflicts of interest to declare.
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Kannt, Aimo, Sridharan Rajagopal, Mahanandeesha S. Hallur, Indu Swamy, Rajendra Kristam, Saravanakumar Dhakshinamoorthy, Joerg Czech, Gernot Zech, Herman Schreuder, and Sven Ruf. "Novel Inhibitors of Nicotinamide-N-Methyltransferase for the Treatment of Metabolic Disorders." Molecules 26, no. 4 (February 13, 2021): 991. http://dx.doi.org/10.3390/molecules26040991.
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Nicotinamide-N-methyltransferase (NNMT) is a cytosolic enzyme catalyzing the transfer of a methyl group from S-adenosyl-methionine (SAM) to nicotinamide (Nam). It is expressed in many tissues including the liver, adipose tissue, and skeletal muscle. Its expression in several cancer cell lines has been widely discussed in the literature, and recent work established a link between NNMT expression and metabolic diseases. Here we describe our approach to identify potent small molecule inhibitors of NNMT featuring different binding modes as elucidated by X-ray crystallographic studies.
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Ramsden, David B., Rosemary H. Waring, Richard B. Parsons, David J. Barlow, and Adrian C. Williams. "Nicotinamide N-Methyltransferase: Genomic Connection to Disease." International Journal of Tryptophan Research 13 (January 2020): 117864692091977. http://dx.doi.org/10.1177/1178646920919770.
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Single-nucleotide polymorphisms (SNPs) in and around the nicotinamide N-methyltransferase (NNMT) gene are associated with a range of cancers and other diseases and conditions. The data on these associations have been assembled, and their strength discussed. There is no evidence that the presence of either the major or minor base in any SNP affects the expression of nicotinamide N-methyltransferase. Nevertheless, suggestions have been put forward that some of these SNPs do affect NNMT expression and thus homocysteine metabolism. An alternative idea involving non-coding messenger RNAs (mRNAs) is suggested as a possible mechanism whereby health is influenced. It is postulated that these long, non-coding NNMT mRNAs may exert deleterious effects by interfering with the expression of other genes. Neither hypothesis, however, has experimental proof, and further work is necessary to elucidate NNMT genetic interactions.
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de Jonge, Robert, Wim J. E. Tissing, Jan Hendrik Hooijberg, Gerrit Jansen, Gertjan J. L. Kaspers, Jan Lindemans, Godefridus J. Peters, and Rob Pieters. "Polymorphisms in folate-related genes and risk of pediatric acute lymphoblastic leukemia." Blood 113, no. 10 (March 5, 2009): 2284–89. http://dx.doi.org/10.1182/blood-2008-07-165928.
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Abstract Polymorphisms in folate pathway genes may influence the susceptibility to acute lymphoblastic leukemia (ALL). DNA was isolated from 245 pediatric ALL patients (cases) and from 500 blood bank donors (controls). Polymorphisms in methylene-tetrahydrofolate reductase (MTHFR 677C>T, 1298A>C), methionine synthase (MTR 2756A>G), methionine synthase reductase (MTRR 66A>G), methylenetetrahydrofolate dehydrogenase (MTHFD1 1958G>A), nicotinamide N-methyltransferase (NNMT IVS −151C>T), serine hydroxymethyl transferase (SHMT1 1420C>T), thymidylate synthase (TS 2R3R), and the reduced folate carrier (RFC1 80G>A) were detected. In ALL patients, an increased occurrence was observed of the RFC1 80AA variant (odds ratio [OR] = 2.1; 95% confidence interval [CI] = 1.3-3.2; P = .002) and the RFC1 80A allele (OR = 1.5; 95% CI, 1.1-2.1; P = .02). Likewise, the NNMT IVS −151TT genotype showed a 2.2-fold increased ALL risk (OR = 2.2; 95% CI, 1.1-4.6; P = .04). A 1.4-fold reduction in ALL risk was observed for (heterozygous or homozygous) carriers of the TS 2R allele and the MTHFR 677T allele (OR = 0.7; 95% CI, 0.5-1.0; P < .05). Furthermore, interactions between NNMT and MTHFR 677C>T and RFC1 were observed. NNMT IVS −151CC/MTHFR 677CT + TT patients exhibited a 2-fold reduction in ALL risk whereas RFC1 80AA/NNMT IVS −151CT + TT subjects had a 4.2-fold increase in ALL risk (P = .001). For the first time, we associate the RFC1 80G>A and NNMT IVS −151C>T variants to an increased ALL susceptibility.
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Kim, Dong Su, Won Sik Ham, Won Sik Jang, Kang Su Cho, Young Deuk Choi, Suki Kang, Bora Kim, et al. "Scale-Up Evaluation of a Composite Tumor Marker Assay for the Early Detection of Renal Cell Carcinoma." Diagnostics 10, no. 10 (September 25, 2020): 750. http://dx.doi.org/10.3390/diagnostics10100750.
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The early detection of renal cell carcinoma (RCC) using tumor markers remains an attractive prospect for the potential to downstage the disease. To validate the scale-up clinical performance of potential tumor markers for RCC (as a single marker and as a composite tumor marker composed of nicotinamide N-methyltransferase (NNMT), L-Plastin (LCP1), and non-metastatic cells 1 protein (NM23A)), the scale-up assay was performed. Patients with RCC from multiple domestic institutes were included in the clinical evaluation for reassessment and improvement of the established triple markers of our product. For the diagnostic performance of the composite markers, the best-split cutoff points of each marker (147 pg/mL for NNMT, 1780 pg/mL for LCP1, and 520 pg/mL for NM23A) were installed. Serum levels of NNMT, LCP1, and NM23A were greatly increased in subjects with RCC (p < 0.0001). In 1042 blind sample tests with control individuals (n = 500) and patients with RCC (n = 542), the diagnostic sensitivity and specificity of the composite three-marker assay were 0.871 and 0.894, respectively, and the resulting AUC (Area under Curve) of ROC (Receiver Operating Characteristic) was 0.917. As a single marker, the diagnostic accuracies of NNMT, LCP1, and NM23A, as estimated by ROC, were 0.833, 0.844, and 0.601, respectively. The composite three-marker assay with NNMT, LCP1, and NM23A is a more improved novel serum marker assay for the early detection of RCC in cases of renal mass or unknown condition. The NNMT, LCP1, and NM23A triple marker assay could be a powerful diagnostic tumor marker assay to screen the early stage of RCC.
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Bai, Zhigang, Dongli Zhang, and Enhong Shi. "Long non-coding RNA opa-interacting protein 5 antisense transcript 1 (LncRNA OIP5-AS1) promoted cisplatin resistance in nasopharyngeal carcinoma via the miR-378a-3p/nicotinamide N-methyltransferase axis." Materials Express 12, no. 7 (July 1, 2022): 980–87. http://dx.doi.org/10.1166/mex.2022.2219.
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LncRNAs involve in chemoresistance of human cancers. However, the role and molecular mechanisms of lncRNA OIP5-AS1 in the chemoresistance of NPC are still unexplored. In our study, upregulated OIP5-AS1 was found in cisplatin (CDDP)-resistant NPC tumors and cell lines. Functional assays revealed OIP5-AS1 knockdown suppressed malignant behaviors, but stimulated apoptosis of CDDP-resistant NPC cells. Furthermore, we demonstrated OIP5-AS1 positively regulated NNMT by directly targeting miR-378a-3p. In addition, its inhibition partially abolished the inhibitory effects of OIP5-AS1 silencing on malignancy of CDDPresistant NPC cells, whereas NNMT knockdown reverse these effects. In sum, our results indicated OIP5-AS1 contributed to the CDDP resistance of NPC by sponging miR-378a-3p to increase NNMT expression.
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Novak Kujundžić, Renata, Marin Prpić, Nikola Đaković, Nina Dabelić, Marko Tomljanović, Anamarija Mojzeš, Ana Fröbe, and Koraljka Gall Trošelj. "Nicotinamide N-Methyltransferase in Acquisition of Stem Cell Properties and Therapy Resistance in Cancer." International Journal of Molecular Sciences 22, no. 11 (May 26, 2021): 5681. http://dx.doi.org/10.3390/ijms22115681.
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The activity of nicotinamide N-methyltransferase (NNMT) is tightly linked to the maintenance of the nicotinamide adenine dinucleotide (NAD+) level. This enzyme catalyzes methylation of nicotinamide (NAM) into methyl nicotinamide (MNAM), which is either excreted or further metabolized to N1-methyl-2-pyridone-5-carboxamide (2-PY) and H2O2. Enzymatic activity of NNMT is important for the prevention of NAM-mediated inhibition of NAD+-consuming enzymes poly–adenosine -diphosphate (ADP), ribose polymerases (PARPs), and sirtuins (SIRTs). Inappropriately high expression and activity of NNMT, commonly present in various types of cancer, has the potential to disrupt NAD+ homeostasis and cellular methylation potential. Largely overlooked, in the context of cancer, is the inhibitory effect of 2-PY on PARP-1 activity, which abrogates NNMT’s positive effect on cellular NAD+ flux by stalling liberation of NAM and reducing NAD+ synthesis in the salvage pathway. This review describes, and discusses, the mechanisms by which NNMT promotes NAD+ depletion and epigenetic reprogramming, leading to the development of metabolic plasticity, evasion of 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.
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Pozzi, Valentina, Roberto Campagna, Davide Sartini, and Monica Emanuelli. "Nicotinamide N-Methyltransferase as Promising Tool for Management of Gastrointestinal Neoplasms." Biomolecules 12, no. 9 (August 24, 2022): 1173. http://dx.doi.org/10.3390/biom12091173.
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Gastrointestinal (GI) neoplasms include esophageal, gastric, colorectal, hepatic, and pancreatic cancers. They are characterized by asymptomatic behavior, being responsible for diagnostic delay. Substantial refractoriness to chemo- and radiotherapy, exhibited by late-stage tumors, contribute to determine poor patient outcome. Therefore, it is of outmost importance to identify new molecular targets for the development of effective therapeutic strategies. In this study, we focused on the enzyme nicotinamide N-methyltransferase (NNMT), which catalyzes the N-methylation reaction of nicotinamide and whose overexpression has been reported in numerous neoplasms, including GI cancers. The aim of this review was to report data illustrating NNMT involvement in these tumors, highlighting its contribution to tumor cell phenotype. Cited works clearly demonstrate the interesting potential use of enzyme level determination for both diagnostic and prognostic purposes. NNMT was also found to positively affect cell viability, proliferation, migration, and invasiveness, contributing to sustain in vitro and in vivo tumor growth and metastatic spread. Moreover, enzyme upregulation featuring tumor cells was significantly associated with enhancement of resistance to treatment with chemotherapeutic drugs. Taken together, these results strongly suggest the possibility to target NNMT for setup of molecular-based strategies to effectively treat GI cancers.
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Zhou, Qiong, Xiao-Juan Zhu, and Jiang-Hua Li. "Association between Nicotinamide N-Methyltransferase Gene Polymorphisms and Obesity in Chinese Han Male College Students." BioMed Research International 2017 (2017): 1–6. http://dx.doi.org/10.1155/2017/2984826.
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Some reports have shown that nicotinamide N-methyltransferase (NNMT) is associated with the body mass index (BMI) and energy metabolism. Here we explored the association between NNMT gene polymorphisms and obesity. The subjects were recruited from male Chinese Han college student. 289 of them (19 ≤ body fat percentage (BF%)) were selected as the high body fat group (HBFG), 494 of them (3 ≤ BF% < 13.5) were selected as the low body fat group (LBFG), and then a case-control study (fat versus thin) was carried out to explore the association between the NNMT gene polymorphism and the body composition using tagSNPs method. A tagSNP (rs10891644) in NNMT gene was found significantly associated with the body composition (P<0.0026). At this locus, the BF% for the genotype GT, TT, and GG were 14.56±8.35, 13.47±8.11, and 12.42±7.50, respectively, and the differences between the GT and the GG + TT were highly significant (P<0.01); the ORadjusted value of the GT versus (GG + TT) was 1.716 (Padjusted=0.002, 95% CI = 1.240–2.235). Therefore, the variation of the tagSNP, rs10891644, is significantly associated with obesity and the GT carriers are the susceptible population.
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DeBasli, Karen L., John H. Newman, Laura J. Sommerville, John A. Phillips, Rizwan Hamid, Joy Cogan, Joshua P. Fessel, Anne M. Evans, and Adam D. Kennedy. "A Case Study of Dysfunctional Nicotinamide Metabolism in a 20-Year-Old Male." Metabolites 13, no. 3 (March 8, 2023): 399. http://dx.doi.org/10.3390/metabo13030399.
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We present a case study of a 20-year-old male with an unknown neurodegenerative disease who was referred to the Undiagnosed Diseases Network Vanderbilt Medical Center site. A previous metabolic panel showed that the patient had a critical deficiency in nicotinamide intermediates that are generated during the biosynthesis of NAD(H). We followed up on these findings by evaluating the patient’s ability to metabolize nicotinamide. We performed a global metabolic profiling analysis of plasma samples that were collected: (1) under normal fed conditions (baseline), (2) after the patient had fasted, and (3) after he was challenged with a 500 mg nasogastric tube bolus of nicotinamide following the fast. Our findings showed that the patient’s nicotinamide N-methyltransferase (NNMT), a key enzyme in NAD(H) biosynthesis and methionine metabolism, was not functional under normal fed or fasting conditions but was restored in response to the nicotinamide challenge. Altered levels of metabolites situated downstream of NNMT and in neighboring biochemical pathways provided further evidence of a baseline defect in NNMT activity. To date, this is the only report of a critical defect in NNMT activity manifesting in adulthood and leading to neurodegenerative disease. Altogether, this study serves as an important reference in the rare disease literature and also demonstrates the utility of metabolomics as a diagnostic tool for uncharacterized metabolic diseases.
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Bockwoldt, Mathias, Dorothée Houry, Marc Niere, Toni I. Gossmann, Ines Reinartz, Alexander Schug, Mathias Ziegler, and Ines Heiland. "Identification of evolutionary and kinetic drivers of NAD-dependent signaling." Proceedings of the National Academy of Sciences 116, no. 32 (July 24, 2019): 15957–66. http://dx.doi.org/10.1073/pnas.1902346116.
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Nicotinamide adenine dinucleotide (NAD) provides an important link between metabolism and signal transduction and has emerged as central hub between bioenergetics and all major cellular events. NAD-dependent signaling (e.g., by sirtuins and poly–adenosine diphosphate [ADP] ribose polymerases [PARPs]) consumes considerable amounts of NAD. To maintain physiological functions, NAD consumption and biosynthesis need to be carefully balanced. Using extensive phylogenetic analyses, mathematical modeling of NAD metabolism, and experimental verification, we show that the diversification of NAD-dependent signaling in vertebrates depended on 3 critical evolutionary events: 1) the transition of NAD biosynthesis to exclusive usage of nicotinamide phosphoribosyltransferase (NamPT); 2) the occurrence of nicotinamide N-methyltransferase (NNMT), which diverts nicotinamide (Nam) from recycling into NAD, preventing Nam accumulation and inhibition of NAD-dependent signaling reactions; and 3) structural adaptation of NamPT, providing an unusually high affinity toward Nam, necessary to maintain NAD levels. Our results reveal an unexpected coevolution and kinetic interplay between NNMT and NamPT that enables extensive NAD signaling. This has implications for therapeutic strategies of NAD supplementation and the use of NNMT or NamPT inhibitors in disease treatment.
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van Haren, Matthijs J., Rebecca Taig, Jilles Kuppens, Javier Sastre Toraño, Ed E. Moret, Richard B. Parsons, Davide Sartini, Monica Emanuelli, and Nathaniel I. Martin. "Inhibitors of nicotinamide N-methyltransferase designed to mimic the methylation reaction transition state." Organic & Biomolecular Chemistry 15, no. 31 (2017): 6656–67. http://dx.doi.org/10.1039/c7ob01357d.
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Campagna, Roberto, Valentina Pozzi, Davide Sartini, Eleonora Salvolini, Valerio Brisigotti, Elisa Molinelli, Anna Campanati, Annamaria Offidani, and Monica Emanuelli. "Beyond Nicotinamide Metabolism: Potential Role of Nicotinamide N-Methyltransferase as a Biomarker in Skin Cancers." Cancers 13, no. 19 (September 30, 2021): 4943. http://dx.doi.org/10.3390/cancers13194943.
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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.
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Sartini, Davide, Valentina Pozzi, Elisabetta Renzi, Stefano Morganti, Romina Rocchetti, Corrado Rubini, Andrea Santarelli, Lorenzo Lo Muzio, and Monica Emanuelli. "Analysis of tissue and salivary nicotinamide N-methyltransferase in oral squamous cell carcinoma: basis for the development of a noninvasive diagnostic test for early-stage disease." Biological Chemistry 393, no. 6 (June 1, 2012): 505–11. http://dx.doi.org/10.1515/hsz-2012-0112.
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Abstract Oral squamous cell carcinoma (OSCC) is the most common form of head and neck cancer worldwide. In recent decades, the 5-year mortality rate is approximately 50% around the world. As reliable biomarkers of oral cancer are still lacking, it is necessary to identify new target molecules for early diagnosis, effective therapy, and monitoring of the disease. In the present work, we focused on the expression of the enzyme nicotinamide N-methyltransferase (NNMT). We analyzed enzyme activity in 37 paired tumor and non-tumor tissues and found that activity levels are significantly higher in tumor compared with adjacent normal oral mucosa. Interestingly, oral epithelium surrounding tumor of unfavorable cases (N+) seems to display higher activity levels compared with that of favorable ones (N0). Western blot analyses were performed to evaluate protein levels in saliva samples from patients with OSCC and healthy subjects. Preliminary results indicated an up-regulation of salivary NNMT in tumor. This study shows a marked increase in enzyme activity in oral cancer and suggests that adjacent normal tissue of unfavorable cases seems to change toward cancer. Moreover, it is conceivable to hypothesize that NNMT could represent a potential biomarker for early and non-invasive diagnosis of oral cancer.
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Hasan, Eman M., Rasha A. Abd Al Aziz, Dina Sabry, Samar K. Darweesh, Hedy A. Badary, Aisha Elsharkawy, Mahmood M. Abouelkhair, and Ayman Yosry. "Genetic Variants in Nicotinamide-N-Methyltransferase (NNMT) Gene are Related to the Stage of Non-Alcoholic Fatty Liver Disease Diagnosed by Controlled Attenuation Parameter (CAP)-FibroScan." Journal of Gastrointestinal and Liver Diseases 27, no. 3 (September 30, 2018): 265–72. http://dx.doi.org/10.15403/jgld.2014.1121.273.wsh.
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Background & Aims: Various genetic polymorphisms play a key-role in the pathogenesis of NAFLD and progression to NASH with fibrosis to cirrhosis. We aimed to study the association between single-nucleotide polymorphisms (SNPs) in NNMT gene, namely rs694539 and the development of different stages of NAFLD diagnosed by controlled attenuation parameter (CAP) of FibroScan Echosens®.
Methods: Transient elastography (FibroScan®) with controlled attenuation parameter (CAP) measurement was performed in 81 NAFLD patients (35 of them with liver biopsy) and 80 non-NAFLD controls. The accuracy of CAP and FibroScan for the detection and quantification of hepatic steatosis/fibrosis, respectively, was assessed based on liver biopsy aspect. Genetic variants of NNMT gene rs694539 were analyzed using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).
Results: According to BMI (kg/m2), among the patients, 17 (21%) were overweight, 56 (69.1%) obese, and 8 (9.9%) morbidly obese. CAP and FibroScan diagnosed steatosis/fibrosis correlated significantly with liver biopsy. There was a significant association between polymorphisms of rs694539-NNMT gene and NAFLD presence and stages. The mutant type (AA-genotype) was found in 33% NAFLD patients versus 1.2% controls (P<0.001), whereas the wild type (GG-genotype) was present in 21% versus 63.8% controls (P<0.001). Moreover, the AA-genotype significantly correlated with the steatosis degree by CAP but not the fibrosis degree by FibroScan. Multivariate regression analysis of all the independent risk factors showed non-significant correlations with the degree of steatosis on CAP. However, by using a stepwise approach, waist circumference showed significance as an independent predictor of NAFLD.
Conclusions: Polymorphisms in rs694539-NNMT gene (mutant AA-genotype) could be a genetic risk factor for developing NAFLD and NASH (indicating susceptibility for progression and complications). Individuals with wild type (GG-genotype) are at less risk of NAFLD development. CAP and FibroScan efficiently diagnosed steatosis and fibrosis.
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Huang, Hao, Guangyuan Zhao, Andres Felipe Valdivia, Horacio Cardenas, Yinu Wang, and Daniela Daniela Matei. "Abstract 5359: M6A regulated NNMT mediates resistance to platinum in ovarian cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5359. http://dx.doi.org/10.1158/1538-7445.am2022-5359.
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Abstract Background: Ovarian cancer (OC) remains one of the deadliest malignancies. Development of resistance to platinum (Pt) is a major clinical problem and understanding its underpinnings will help find new approaches to overcome it. Fat mass and obesity associated protein (FTO) is a N6-methyladenosine (m6A) demethylase and plays an important role regulating how the messenger RNA is processed translating into functional proteins. We recently showed that m6A modifications induced by FTO play a suppressive role in tumorigenicity and survival of OC stem cells. Here we hypothesized that RNA modifications caused by FTO regulate the response of OC cells to Pt. Methods: To study the mechanisms related to FTO implicated in response to Pt; we used OC cells in which FTO was knocked down (KD) via shRNA or overexpressed (OE). Additionally, Pt-resistant (Pt-R) OC cells were obtained through repeated (3-4) exposures to Pt. Cell viability assay determined the IC50 (half maximal inhibitory concentration) to Pt. Pt response in vivo was assessed in FTO expressing vs. FTO KD xenografts. Induction of DNA damage was assessed by immunofluorescence (IF) for γ-H2AX. Apoptosis was evaluated by Annexin V staining in the IncuCyte system. To identify potential targets of FTO-mediated m6A modifications in Pt induced response, RNA-seq and MeRIP-seq were integrated. Results: FTO was significantly downregulated in Pt-R vs. sensitive OC cells. Forced expression of FTO increased sensitivity to Pt in vitro and in vivo, while FTO KD increased Pt resistance (p<0.05). A catalytic mutant FTO did not appreciably alter responsiveness to Pt. Increased γ-H2AX foci and increased apoptosis were observed after exposure to Pt in FTO OE vs. control cells. Through integrated RNA-seq and MeRIP-seq, we identified and validated several potential targets involved in response to Pt including IER5, IER5, ST3Gal, and the enzyme nicotinamide N-methyltransferase (NNMT). NNMT was upregulated and significantly hypomethylated in FTO OE cells and was downregulated in Pt resistant cells. Treatment with an NNMT inhibitor rescued the FTO induced sensitivity to Pt in OC cells demonstrating that its function is necessary in the response to Pt. Conclusions: We identified a new function of FTO-dependent m6A RNA modifications in regulating response to Pt through NNMT, a novel RNA methylated target. Activating FTO could improve response to Pt in OC. Citation Format: Hao Huang, Guangyuan Zhao, Andres Felipe Valdivia, Horacio Cardenas, Yinu Wang, Daniela Daniela Matei. M6A regulated NNMT mediates resistance to platinum in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5359.
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Babault, Nicolas, Abdellah Allali-Hassani, Fengling Li, Jie Fan, Alex Yue, Kevin Ju, Feng Liu, Masoud Vedadi, Jing Liu, and Jian Jin. "Discovery of Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT)." Journal of Medicinal Chemistry 61, no. 4 (January 31, 2018): 1541–51. http://dx.doi.org/10.1021/acs.jmedchem.7b01422.
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Gao, Yongzhi, Matthijs J. van Haren, Ed E. Moret, Johannes J. M. Rood, Davide Sartini, Alessia Salvucci, Monica Emanuelli, et al. "Bisubstrate Inhibitors of NicotinamideN-Methyltransferase (NNMT) with Enhanced Activity." Journal of Medicinal Chemistry 62, no. 14 (July 2, 2019): 6597–614. http://dx.doi.org/10.1021/acs.jmedchem.9b00413.
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Liu, Wenxiu, Hongyan Gou, Xiaohong Wang, Xiaoming Li, Xiaoxu Hu, Hao Su, Shengmian Li, and Jun Yu. "TTPAL promotes gastric tumorigenesis by directly targeting NNMT to activate PI3K/AKT signaling." Oncogene 40, no. 49 (October 12, 2021): 6666–79. http://dx.doi.org/10.1038/s41388-021-01838-x.
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AbstractCopy number alterations are crucial for gastric cancer (GC) development. In this study, Tocopherol alpha transfer protein-like (TTPAL) was identified to be highly amplified in our primary GC cohort (30/86). Multivariate analysis showed that high TTPAL expression was correlated with the poor prognosis of GC patients. Ectopic expression of TTPAL promoted GC cell proliferation, migration, and invasion in vitro and promoted murine xenograft tumor growth and lung metastasis in vivo. Conversely, silencing of TTPAL exerted significantly opposite effects in vitro. Moreover, RNA-sequencing and co-immunoprecipitation (Co-IP) followed by liquid chromatograph-mass spectrometry (LC-MS) identified that TTPAL exerted oncogenic functions via the interaction of Nicotinamide-N-methyl transferase (NNMT) and activated PI3K/AKT signaling pathway. Collectively, TTPAL plays a pivotal oncogenic role in gastric carcinogenesis through promoting PI3K/AKT pathway via cooperating with NNMT. TTPAL may serve as a prognostic biomarker of patients with GC.
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Zhu, Xiao-Juan, Ya-Jun Lin, Wei Chen, Ya-Hui Wang, Li-Qiang Qiu, Can-Xin Cai, Qun Xiong, et al. "Physiological Study on Association between Nicotinamide N-Methyltransferase Gene Polymorphisms and Hyperlipidemia." BioMed Research International 2016 (2016): 1–8. http://dx.doi.org/10.1155/2016/7521942.
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Nicotinamide N-methyltransferase (NNMT) catalyzes the methylation of nicotinamide. Our previous works indicate that NNMT is involved in the body mass index and energy metabolism, and recently the association between a SNP (rs694539) ofNNMTand a variety of cardiovascular diseases was reported. At present, more than 200NNMTsingle nucleotide polymorphisms (SNPs) have been identified in the databases of the human genome projects; however, the association between rs694539 variation and hyperlipidemia has not been reported yet, and whether there are any SNPs inNNMTsignificantly associated with hyperlipidemia is still unclear. In this paper, we selected 19 SNPs inNNMTas the tagSNPs using Haploview software (Haploview 4.2) first and then performed a case-control study to observe the association between these tagSNPs and hyperlipidemia and finally applied physiological approaches to explore the possible mechanisms through which theNNMTpolymorphism induces hyperlipidemia. The results show that a SNP (rs1941404) inNNMTis significantly associated with hyperlipidemia, and the influence of rs1941404 variation on the resting energy expenditure may be the possible mechanism for rs1941404 variation to induce hyperlipidemia.
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Rivas, Maria Prates, Talita Ferreira Marques Aguiar, Mariana Maschietto, Renan B. Lemes, Luiz Carlos Caires-Júnior, Ernesto Goulart, Kayque Alves Telles-Silva, et al. "Hepatoblastomas exhibit marked NNMT downregulation driven by promoter DNA hypermethylation." Tumor Biology 42, no. 12 (November 30, 2020): 101042832097712. http://dx.doi.org/10.1177/1010428320977124.
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Hepatoblastomas exhibit the lowest mutational burden among pediatric tumors. We previously showed that epigenetic disruption is crucial for hepatoblastoma carcinogenesis. Our data revealed hypermethylation of nicotinamide N-methyltransferase, a highly expressed gene in adipocytes and hepatocytes. The expression pattern and the role of nicotinamide N-methyltransferase in pediatric liver tumors have not yet been explored, and this study aimed to evaluate the effect of nicotinamide N-methyltransferase hypermethylation in hepatoblastomas. We evaluated 45 hepatoblastomas and 26 non-tumoral liver samples. We examined in hepatoblastomas if the observed nicotinamide N-methyltransferase promoter hypermethylation could lead to dysregulation of expression by measuring mRNA and protein levels by real-time quantitative polymerase chain reaction, immunohistochemistry, and Western blot assays. The potential impact of nicotinamide N-methyltransferase changes was evaluated on the metabolic profile by high-resolution magic angle spinning nuclear magnetic resonance spectroscopy. Significant nicotinamide N-methyltransferase downregulation was revealed in hepatoblastomas, with two orders of magnitude lower nicotinamide N-methyltransferase expression in tumor samples and hepatoblastoma cell lines than in hepatocellular carcinoma cell lines. A specific TSS1500 CpG site (cg02094283) of nicotinamide N-methyltransferase was hypermethylated in tumors, with an inverse correlation between its methylation level and nicotinamide N-methyltransferase expression. A marked global reduction of the nicotinamide N-methyltransferase protein was validated in tumors, with strong correlation between gene and protein expression. Of note, higher nicotinamide N-methyltransferase expression was statistically associated with late hepatoblastoma diagnosis, a known clinical variable of worse prognosis. In addition, untargeted metabolomics analysis detected aberrant lipid metabolism in hepatoblastomas. Data presented here showed the first evidence that nicotinamide N-methyltransferase reduction occurs in hepatoblastomas, providing further support that the nicotinamide N-methyltransferase downregulation is a wide phenomenon in liver cancer. Furthermore, this study unraveled the role of DNA methylation in the regulation of nicotinamide N-methyltransferase expression in hepatoblastomas, in addition to evaluate the potential effect of nicotinamide N-methyltransferase reduction in the metabolism of these tumors. These preliminary findings also suggested that nicotinamide N-methyltransferase level may be a potential prognostic biomarker for hepatoblastoma.
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Lo Muzio, L., L. Lo Russo, A. Santarelli, D. Sartini, C. Rubini, C. Di Liberto, O. Di Fede, V. Rossi, and M. Emanuelli. "P249 NNMT expression and prognosis in oral squamous cell carcinoma." Oral Oncology Supplement 2, no. 1 (May 2007): 206. http://dx.doi.org/10.1016/s1744-7895(07)70526-6.
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Policarpo, Rocco L., Ludovic Decultot, Elizabeth May, Petr Kuzmič, Samuel Carlson, Danny Huang, Vincent Chu, et al. "High-Affinity Alkynyl Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT)." Journal of Medicinal Chemistry 62, no. 21 (October 7, 2019): 9837–73. http://dx.doi.org/10.1021/acs.jmedchem.9b01238.
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Trammell, Samuel A. J., and Charles Brenner. "NNMT: A Bad Actor in Fat Makes Good in Liver." Cell Metabolism 22, no. 2 (August 2015): 200–201. http://dx.doi.org/10.1016/j.cmet.2015.07.017.
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van Haren, Matthijs J., Yongzhi Gao, Ned Buijs, Roberto Campagna, Davide Sartini, Monica Emanuelli, Lukasz Mateuszuk, et al. "Esterase-Sensitive Prodrugs of a Potent Bisubstrate Inhibitor of Nicotinamide N-Methyltransferase (NNMT) Display Cellular Activity." Biomolecules 11, no. 9 (September 14, 2021): 1357. http://dx.doi.org/10.3390/biom11091357.
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A recently discovered bisubstrate inhibitor of Nicotinamide N-methyltransferase (NNMT) was found to be highly potent in biochemical assays with a single digit nanomolar IC50 value but lacking in cellular activity. We, here, report a prodrug strategy designed to translate the observed potent biochemical inhibitory activity of this inhibitor into strong cellular activity. This prodrug strategy relies on the temporary protection of the amine and carboxylic acid moieties of the highly polar amino acid side chain present in the bisubstrate inhibitor. The modification of the carboxylic acid into a range of esters in the absence or presence of a trimethyl-lock (TML) amine protecting group yielded a range of candidate prodrugs. Based on the stability in an aqueous buffer, and the confirmed esterase-dependent conversion to the parent compound, the isopropyl ester was selected as the preferred acid prodrug. The isopropyl ester and isopropyl ester-TML prodrugs exhibit improved cell permeability, which also translates to significantly enhanced cellular activity as established using assays designed to measure the enzymatic activity of NNMT in live cells.
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Williams, Adrian C., Lisa J. Hill, and David B. Ramsden. "Nicotinamide, NAD(P)(H), and Methyl-Group Homeostasis Evolved and Became a Determinant of Ageing Diseases: Hypotheses and Lessons from Pellagra." Current Gerontology and Geriatrics Research 2012 (2012): 1–24. http://dx.doi.org/10.1155/2012/302875.
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Compartmentalized redox faults are common to ageing diseases. Dietary constituents are catabolized to NAD(H) donating electrons producing proton-based bioenergy in coevolved, cross-species and cross-organ networks. Nicotinamide and NAD deficiency from poor diet or high expenditure causes pellagra, an ageing and dementing disorder with lost robustness to infection and stress. Nicotinamide and stress induce Nicotinamide-N-methyltransferase (NNMT) improving choline retention but consume methyl groups. High NNMT activity is linked to Parkinson’s, cancers, and diseases of affluence. Optimising nicotinamide and choline/methyl group availability is important for brain development and increased during our evolution raising metabolic and methylome ceilings through dietary/metabolic symbiotic means but strict energy constraints remain and life-history tradeoffs are the rule. An optimal energy, NAD and methyl group supply, avoiding hypo and hyper-vitaminoses nicotinamide and choline, is important to healthy ageing and avoids utilising double-edged symbionts or uncontrolled autophagy or reversions to fermentation reactions in inflammatory and cancerous tissue that all redistribute NAD(P)(H), but incur high allostatic costs.
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Sabnis, Ram W. "Novel Pyrimidine-5-carboxamide Compounds as NNMT Inhibitors for Treating Diabetes." ACS Medicinal Chemistry Letters 12, no. 4 (March 26, 2021): 538–39. http://dx.doi.org/10.1021/acsmedchemlett.1c00150.
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Kanska, Justyna, Paul-Joseph P. Aspuria, Barbie Taylor-Harding, Lindsay Spurka, Vincent Funari, Sandra Orsulic, Beth Y. Karlan, and W. Ruprecht Wiedemeyer. "Glucose deprivation elicits phenotypic plasticity via ZEB1-mediated expression of NNMT." Oncotarget 8, no. 16 (February 17, 2017): 26200–26220. http://dx.doi.org/10.18632/oncotarget.15429.
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