Nicotinamide N-methyltransferase enhances the capacity of tumorigenesis associated with the promotion of cell cycle progression in human colorectal cancer cells

Xie, Xinyou; Yu, Haitao; Wang, Yanzhong; Zhou, Yi; Li, Guiling; Ruan, Zhi; Li, Fengying; Wang, Xiuhong; Liu, Huixing; Zhang, Jun

doi:10.1016/j.abb.2014.08.017

Cited by 60 publications

(85 citation statements)

References 36 publications

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“…Our recent studies have shown that NNMT enhances tumorigenesis in human CRC cells by inhibiting apoptosis and promoting cell cycle progression, and that the cellular effect of NNMT is mediated by the produced 1-methylnicotinamide (1-MNA) [15]. Our results have suggested that NNMT is involved in energy balance and ROS production, and is associated with PI3K/Akt and MAPK pathways activation.…”

Section: Introductionmentioning

confidence: 68%

“…We have previously shown that NNMT reduces the intracellular ROS levels in CRC cells [15]. To explore the potential mechanism responsible for the AKS1 inactivation by NNMT in 5-FU treated CRC cells, we have analyzed the intracellular ROS, which can activate ASK1 by dissociating it from glutathione-S-transferase (GST).…”

Section: Resultsmentioning

confidence: 99%

“…We have previously shown that NNMT decreases the intracellular levels of ROS via 1-MNA, the metabolic product of NNMT [15]. To investigate the function of NNMT in 5-FU-treated CRC cells, we analyzed the intracellular 1-MNA levels.…”

Section: Resultsmentioning

confidence: 99%

“…Our recent study has shown that NNMT overexpression increases cell survival, proliferation, colony formation, cell cycle progression, and intracellular ATP levels in CRC cells, and promotes tumorigenicity in mice [15]. Since suppression of NNMT inhibits proliferation of several types of human carcinoma cells [15–19], NNMT may become a possible molecular target for anti-cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

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Nicotinamide N-methyltransferase enhances resistance to 5-fluorouracil in colorectal cancer cells through inhibition of the ASK1-p38 MAPK pathway

et al. 2016

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Nicotinamide N-methyltransferase (NNMT), which converts nicotinamide to 1-methylnicotinamide (1-MNA), is overexpressed in a variety of human cancers and serves as a potential anti-cancer target. In this study, we investigated the effect of NNMT on 5-fluorouracil (5-FU) sensitivity of colorectal cancer (CRC) cells, and the underlying mechanisms. Our results show that down-regulation of NNMT in CRC HT-29 cells diminishes 5-FU resistance, while over expression of NNMT in SW480 cells enhances it. NNMT reduces reactive oxygen species (ROS) production induced by 5-FU by increasing 1-MNA in CRC cells. The reduction in ROS leads to inactivation of the ASK1-p38 mitogen-activated protein kinase (MAPK) pathway, which reduces 5-FU-induced apoptosis. In vivo, NNMT attenuates 5-FU-induced inhibition of CRC tumor growth in nude mice. These observations suggest that NNMT and the 1-MNA it produces inhibit the ASK1-p38 MAPK pathway, resulting in increased CRC cell resistance to 5-FU.

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Section: Introductionmentioning

confidence: 68%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Nicotinamide N-methyltransferase enhances resistance to 5-fluorouracil in colorectal cancer cells through inhibition of the ASK1-p38 MAPK pathway

et al. 2016

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“…It is possible that MeN, the metabolic product of NNMT N-methylation of nicotinamide, may be responsible, which is supported by our previous studies that demonstrated that MeN increased CxI activity and cellular ATP content in SH-SY5Y cells [10,11]. In accord with this, Xie et al [33] reported that increased MeN production was responsible for the NNMTmediated increase in cellular ATP content in human colorectal cancer cells. SirTs are also thought to act as metabolic sensors via their use of NAD+ as substrate [16,17], whose availability is regulated by NNMT via NAD+ synthesis [3,34].…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 54%

Nicotinamide N-methyltransferase increases complex I activity in SH-SY5Y cells via sirtuin 3

Liu

Mistry

Aguirre

et al. 2015

Biochemical and Biophysical Research Communications

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Nicotinamide N-methyltransferase (NNMT, E.C. 2.1.1.1) N-methylates nicotinamide to 1-methylnicotinamide. We have previously shown that NNMT is significantly overexpressed in the brains of patients who have died of Parkinson's disease, and others have shown that NNMT is significantly overexpressed in a variety of diseases ranging from cancer to hepatic cirrhosis. In vitro overexpression has revealed many cytoprotective effects of NNMT, in particular increased complex I activity and ATP synthesis. Although this appears to be mediated by an increase in 1-methylnicotinamide production, the molecular mechanisms involved remain unclear. In the present study, we have investigated the role that sirtuins 1, 2 and 3, class III DNA deacetylase enzymes known to regulate mitochondrial energy production and cell cycle, have in mediating the effects of NNMT upon complex I activity. Expression of NNMT in SH-SY5Y human neuroblastoma cells, which have no endogenous expression of NNMT, significantly increased the expression of all three sirtuins. siRNA-mediated silencing of sirtuin 3 expression decreased complex I activity in NNMT-expressing SH-SY5Y cells to that observed in wild-type SH-SY5Y, and significantly reduced cellular ATP content also. These results demonstrate that sirtuin 3 is a key mediator of NNMT-induced complex I activity and ATP synthesis. These results further reinforce a central role for NNMT in the regulation of energy homeostasis and provide further mechanistic insight into the consequences of enhanced NNMT expression.

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NNMT/1‐MNA Promote Cell‐Cycle Progression of Breast Cancer by Targeting UBC12/Cullin‐1‐Mediated Degradation of P27 Proteins

Ma,

Huang,

Wang

et al. 2023

Advanced Science

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Cell cycle dysregulation is a defining feature of breast cancer. Here, 1‐methyl‐nicotinamide (1‐MNA), metabolite of nicotinamide N‐methyltransferase(NNMT) is identified, as a novel driver of cell‐cycle progression in breast cancer. NNMT, highly expressed in breast cancer tissues, positively correlates with tumor grade, TNM stage, Ki‐67 index, and tumor size. Ablation of NNMT expression dramatically suppresses cell proliferation and causes cell‐cycle arrest in G0/G1 phase. This phenomenon predominantly stems from the targeted action of 1‐MNA, resulting in a specific down‐regulation of p27 protein expression. Mechanistically, 1‐MNA expedites the degradation of p27 proteins by enhancing cullin‐1 neddylation, crucial for the activation of Cullin‐1‐RING E3 ubiquitin ligase(CRL1)—an E3 ubiquitin ligase targeting p27 proteins. NNMT/1‐MNA specifically up‐regulates the expression of UBC12, an E2 NEDD8‐conjugating enzyme required for cullin‐1 neddylation. 1‐MNA showes high binding affinity to UBC12, extending the half‐life of UBC12 proteins via preventing their localization to lysosome for degradation. Therefore, 1‐MNA is a bioactive metabolite that promotes breast cancer progression by reinforcing neddylation pathway‐mediated p27 degradation. The study unveils the link between NNMT enzymatic activity with cell‐cycle progression, indicating that 1‐MNA may be involved in the remodeling of tumor microenvironment.

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Nicotinamide N-methyltransferase enhances the capacity of tumorigenesis associated with the promotion of cell cycle progression in human colorectal cancer cells

Cited by 60 publications

References 36 publications

Nicotinamide N-methyltransferase enhances resistance to 5-fluorouracil in colorectal cancer cells through inhibition of the ASK1-p38 MAPK pathway

Nicotinamide N-methyltransferase enhances resistance to 5-fluorouracil in colorectal cancer cells through inhibition of the ASK1-p38 MAPK pathway

Nicotinamide N-methyltransferase increases complex I activity in SH-SY5Y cells via sirtuin 3

NNMT/1‐MNA Promote Cell‐Cycle Progression of Breast Cancer by Targeting UBC12/Cullin‐1‐Mediated Degradation of P27 Proteins

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