Nicotinamide N-methyltransferase overexpression may be associated with poor prognosis in ovarian cancer

Harmankaya, Ísmail; Akar, Serra; Uğraş, Serdar; Güler, Abdül Hamid; Ezveci, Huriye; Aydoğdu, Meltem; Çelık, Çetin

doi:10.1080/01443615.2020.1732891

Cited by 17 publications

(18 citation statements)

References 16 publications

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“…Proteomic analysis revealed that NNMT is also highly expressed in ovarian, breast and colon cancer metastasis-associated stroma [ 61 ]. NNMT expression progressively increases in the stroma of ovarian neoplasms, and protein overexpression is independently associated with poor prognosis [ 74 ]. Moreover, it has been demonstrated that elevated NNMT levels can be used for early diagnosis in some malignant tumors and as a non-invasive biomarker of cancer in body fluids, including serum saliva and urine [ [75] , [76] , [77] ].…”

Section: Nnmt As a Cancer-associated Metabolic Enzymementioning

confidence: 99%

Nicotinamide N-methyltransferase: At the crossroads between cellular metabolism and epigenetic regulation

Roberti

Fernández

Fraga

2021

Molecular Metabolism

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Background The abundance of energy metabolites is intimately interconnected with the activity of chromatin-modifying enzymes in order to guarantee the finely tuned modulation of gene expression in response to cellular energetic status. Metabolism-induced epigenetic gene regulation is a key molecular axis for the maintenance of cellular homeostasis, and its deregulation is associated with several pathological conditions. Nicotinamide N-methyltransferase (NNMT) is a metabolic enzyme that catalyzes the methylation of nicotinamide (NAM) using the universal methyl donor S-adenosyl methionine (SAM), directly linking one-carbon metabolism with a cell's methylation balance and nicotinamide adenine dinucleotide (NAD + ) levels. NNMT expression and activity are regulated in a tissue-specific-manner, and the protein can act either physiologically or pathologically depending on its distribution. While NNMT exerts a beneficial effect by regulating lipid parameters in the liver, its expression in adipose tissue correlates with obesity and insulin resistance. NNMT upregulation has been observed in a variety of cancers, and increased NNMT expression has been associated with tumor progression, metastasis and worse clinical outcomes. Accordingly, NNMT represents an appealing druggable target for metabolic disorders as well as oncological and other diseases in which the protein is improperly activated. Scope of review This review examines emerging findings concerning the complex NNMT regulatory network and the role of NNMT in both NAD metabolism and cell methylation balance. We extensively describe recent findings concerning the physiological and pathological regulation of NNMT with a specific focus on the function of NNMT in obesity, insulin resistance and other associated metabolic disorders along with its well-accepted role as a cancer-associated metabolic enzyme. Advances in strategies targeting NNMT pathways are also reported, together with current limitations of NNMT inhibitor drugs in clinical use. Major conclusions NNMT is emerging as a key point of intersection between cellular metabolism and epigenetic gene regulation, and growing evidence supports its central role in several pathologies. The use of molecules that target NNMT represents a current pharmaceutical challenge for the treatment of several metabolic-related disease as well as in cancer.

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Section: Nnmt As a Cancer-associated Metabolic Enzymementioning

confidence: 99%

Nicotinamide N-methyltransferase: At the crossroads between cellular metabolism and epigenetic regulation

Roberti

Fernández

Fraga

2021

Molecular Metabolism

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“…Aberrant NNMT activation has also been observed in various cancers and is correlated with worse clinical outcomes, such as ovarian cancer, 44 colorectal cancer 45 and human esophageal squamous cell carcinoma 46 . NNMT reduces ROS generation and lipid peroxidation in human neuroblastoma cells 47 .…”

Section: Discussionmentioning

confidence: 99%

Nicotinamide N‐methyltransferase ameliorates renal fibrosis by its metabolite 1‐methylnicotinamide inhibiting the TGF‐β1/Smad3 pathway

Zhang

Rong

et al. 2022

The FASEB Journal

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Chronic kidney disease (CKD), a disease involving damage to the kidney structure and function, is a global public health problem. Tubulointerstitial fibrosis (TIF) is both an inevitable pathological change in individuals with CKD and a driving force in the progression of renal fibrosis. Nicotinamide N‐methyltransferase (NNMT) and its metabolite 1‐methylnicotinamide (MNAM) have been shown to protect against lipotoxicity‐induced kidney tubular injury. However, the biological roles of NNMT and MNAM in regulating TIF remain elusive. This study aimed to investigate the protective effect of NNMT and MNAM on TIF and the mechanisms involved. We explored the functions and mechanisms of NNMT and MNAM in TIF, as well as the interaction between NNMT and MNAM, using unilateral ureteral obstruction (UUO) mice and cultured mouse tubular epithelial cells (mTECs) stimulated with transforming growth factor‐β1 (TGF‐β1). Several important findings were obtained as follows: (1) NNMT expression was upregulated in the kidneys of UUO mice and TGF‐β1‐induced mTECs, and this upregulation was proposed to be a protective compensatory response to TIF. (2) MNAM was a potentially effective antifibrotic and anti‐inflammatory medication in UUO mice. (3) The antifibrotic effect of NNMT overexpression was exerted by increasing the concentration of MNAM. (4) The renoprotective role of MNAM depended on the selective blockade of the interaction of Smad3 with TGFβ receptor I. Overall, our study shows that NNMT is involved in the development and progression of CKD and that its metabolite MNAM may be a novel inhibitor of the TGF‐β1/Smad3 pathway with great therapeutic potential for CKD.

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“…NNMT expression is altered in metabolic diseases such as obesity and cirrhosis ( 11 ). In addition, a wide range of studies have shown that NNMT is elevated in various cancers, including squamous cell carcinoma (SCC) ( 27 ), colorectal cancer ( 12 ), renal cell carcinoma ( 28 ), bladder cancer ( 29 ), ovarian cancer ( 30 ), cutaneous malignant melanoma (CMM) ( 31 ), gastric cancer ( 32 ), pancreatic cancer ( 33 , 34 ), and glioblastoma (GBM) ( 7 ). Interestingly, NNMT expression was elevated in atorvastatin- and pravastatin-treated endothelial cells, which elevated nitric oxide and reactive oxygen species (ROS) ( 35 ).…”

Section: Nnmt Expression and Gene Structurementioning

confidence: 99%

“…Considering that NNMT is elevated in various cancers, most studies on NNMT have focused on its early diagnostic role ( 27 , 38 , 39 ). It is worth noting that some experiments have revealed increased NNMT expression in body fluids, including blood, urine, and saliva ( 12 , 13 , 40 ).…”

Section: Association Between Nnmt Expression and Poor Cancer Prognosismentioning

confidence: 99%

Nicotinamide N-Methyltransferase: A Promising Biomarker and Target for Human Cancer Therapy

Chen

et al. 2022

Front. Oncol.

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Cancer cells typically exhibit a tightly regulated program of metabolic plasticity and epigenetic remodeling to meet the demand of uncontrolled cell proliferation. The metabolic–epigenetic axis has recently become an increasingly hot topic in carcinogenesis and offers new avenues for innovative and personalized cancer treatment strategies. NicotinamideN-methyltransferase (NNMT) is a metabolic enzyme involved in controlling methylation potential, impacting DNA and histone epigenetic modification.NNMToverexpression has been described in various solid cancer tissues and even body fluids, including serum, urine, and saliva. Furthermore, accumulating evidence has shown thatNNMTknockdown significantly decreases tumorigenesis and chemoresistance capacity. Most importantly, the natural NNMT inhibitor yuanhuadine can reverse epidermal growth factor receptor tyrosine kinase inhibitor resistance in lung cancer cells. In this review, we evaluate the possibility of NNMT as a diagnostic biomarker and molecular target for effective anticancer treatment. We also reveal the exact mechanisms of how NNMT affects epigenetics and the development of more potent and selective inhibitors.

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Nicotinamide N-methyltransferase overexpression may be associated with poor prognosis in ovarian cancer

Cited by 17 publications

References 16 publications

Nicotinamide N-methyltransferase: At the crossroads between cellular metabolism and epigenetic regulation

Nicotinamide N-methyltransferase: At the crossroads between cellular metabolism and epigenetic regulation

Nicotinamide N‐methyltransferase ameliorates renal fibrosis by its metabolite 1‐methylnicotinamide inhibiting the TGF‐β1/Smad3 pathway

Nicotinamide N-Methyltransferase: A Promising Biomarker and Target for Human Cancer Therapy

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