Advances in the role of nicotinamide N-methyltransferase in gastric cancer and related mechanisms_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

JING Siqing , ZHENG Xiaolong ,  WANG Meng

Department of Gastrointestinal and Hernia Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Medical School of Nanjing University, Nanjing 210008, P. R. China;

Corresponding author：

WANG Meng, Email: wangmeng1980@nju.edu.cn

Keywords：

gastric cancer; nicotinamide N-methyltransferase; cellular metabolism; targeted therapy

DOI：

10.7507/1007-9424.202409063

Video：

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Objective To systematically review the role and potential clinical value of nicotinamide N-methyltransferase (NNMT) in gastric cancer, aiming to provide new insights for diagnosis, treatment, and prognosis of gastric cancer. Methods Relevant literature from recent years on the involvement of NNMT in gastric cancer was thoroughly analyzed. The review focuses on the mechanisms by which NNMT influences cell proliferation, invasion, migration, and metabolic reprogramming in gastric cancer. Additionally, the study explores the potential of NNMT as a diagnostic and therapeutic target. Results NNMT was significantly overexpressed in gastric cancer tissues and was closely associated with tumor progression. It promoted malignant behaviors through various pathways, including metabolic regulation, enhancement of cancer cell proliferation and invasion, and alteration of the tumor microenvironment. Furthermore, NNMT played a crucial role in modulating host immune responses, which might impact the clinical prognosis of gastric cancer patients. Conclusions NNMT exhibits significant biological functions in the development and progression of gastric cancer. As a potential biomarker and therapeutic target, it holds promising clinical value in the diagnosis and targeted treatment of gastric cancer, providing new strategies and evidence for precision therapy and prognosis assessment.

1.	李茁钰, 刘凯, 张维汉, 等. 全球及中国胃癌的流行病学特点及趋势: 2018–2022《全球癌症统计报告》解读. 中国普外基础与临床杂志, 2024, 31(10): 1236-1245.
2.	姚一菲, 孙可欣, 郑荣寿. 《2022全球癌症统计报告》解读: 中国与全球对比. 中国普外基础与临床杂志, 2024, 31(7): 769-780.
3.	Wu C, Liu Y, Liu W, et al. NNMT-DNMT1 axis is essential for maintaining cancer cell sensitivity to oxidative phosphorylation inhibition. Adv Sci (Weinh), 2022, 10(1): e2202642. doi: 10.1002/advs.202202642.
4.	Ma Y, Huang X, Wang Y, et al. NNMT/1-MNA promote cell-cycle progression of breast cancer by targeting UBC12/cullin-1-mediated degradation of P27 proteins. Adv Sci (Weinh), 2024, 11(9): e2305907. doi: 10.1002/advs.202305907.
5.	Alston TA, Abeles RH. Substrate specificity of nicotinamide methyltransferase isolated from porcine liver. Arch Biochem Biophys, 1988, 260(2): 601-608.
6.	Barrows RD, Jeffries DE, Vishe M, et al. Potent uncompetitive inhibitors of nicotinamide N-methyltransferase (NNMT) as In Vivo Chemical Probes. J Med Chem, 2022, 65(21): 14642-14654.
7.	Perez MF, Sarkies P. Histone methyltransferase activity affects metabolism in human cells independently of transcriptional regulation. PLoS Biol, 2023, 21(10): e3002354. doi: 10.1371/journal.pbio.3002354.
8.	Davalieva K, Kiprijanovska S, Ivanovski O, et al. Proteomics profiling of bladder cancer tissues from early to advanced stages reveals NNMT and GALK1 as biomarkers for early detection and prognosis of BCa. Int J Mol Sci, 2023, 24(19): 14938. doi:10.3390/ijms241914938.
9.	Nguyen TTM, Nguyen TH, Kim HS, et al. GPX8 regulates clear cell renal cell carcinoma tumorigenesis through promoting lipogenesis by NNMT. J Exp Clin Cancer Res, 2023, 42(1): 42. doi: 10.1186/s13046-023-02607-2.
10.	Campagna R, Salvolini E, Pompei V, et al. Nicotinamide N-methyltransferase gene silencing enhances chemosensitivity of melanoma cell lines. Pigment Cell Melanoma Res, 2021, 34(6): 1039-1048.
11.	Wang J, Liu X, Huang Y, et al. Targeting nicotinamide N-methyltransferase overcomes resistance to EGFR-TKI in non-small cell lung cancer cells. Cell Death Discov, 2022, 8(1): 170. doi: 10.1038/s41420-022-00966-x.
12.	Huang Q, Chen H, Yin D, et al. Multi-omics analysis reveals NNMT as a master metabolic regulator of metastasis in esophageal squamous cell carcinoma. NPJ Precis Oncol, 2024, 8(1): 24. doi: 10.1038/s41698-024-00509-w.
13.	Eckert MA, Coscia F, Chryplewicz A, et al. Proteomics reveals NNMT as a master metabolic regulator of cancer-associated fibroblasts. Nature, 2019, 569(7758): 723-728.
14.	Yu X, Zhang N, Wu J, et al. Predictive value of adipokines for the severity of acute pancreatitis: a meta-analysis. BMC Gastroenterol, 2024, 24(1): 32. doi: 10.1186/s12876-024-03126-w.
15.	Wang Z, Wang Q, Chen C, et al. NNMT enriches for AQP5⁺ cancer stem cells to drive malignant progression in early gastric cardia adenocarcinoma. Gut, 2023, 73(1): 63-77.
16.	Chen C, Wang X, Huang X, et al. Nicotinamide N-methyltransferase: a potential biomarker for worse prognosis in gastric carcinoma. Am J Cancer Res, 2016, 6(3): 649-663.
17.	田恒金, 汪非凡, 高培垚, 等. 自噬在胃癌干细胞中的作用及研究进展. 中国现代医生, 2024, 62(6): 120-123.
18.	Cui Y, Zhang L, Wang W, et al. Downregulation of nicotinamide N-methyltransferase inhibits migration and epithelial-mesenchymal transition of esophageal squamous cell carcinoma via Wnt/β-catenin pathway. Mol Cell Biochem, 2019, 460(1-2): 93-103.
19.	Uribe-Etxebarria V, Pineda JR, García-Gallastegi P, et al. Notch and Wnt signaling modulation to enhance DPSC stemness and therapeutic potential. Int J Mol Sci, 2023, 24(8): 7389. doi: 10.3390/ijms24087389.
20.	Tan SH, Swathi Y, Tan S, et al. AQP5 enriches for stem cells and cancer origins in the distal stomach. Nature, 2020, 578(7795): 437-443.
21.	Koushyar S, Powell AG, Vincan E, et al. Targeting Wnt signaling for the treatment of gastric cancer. Int J Mol Sci, 2020, 21(11): 3927. doi: 10.3390/ijms21113927.
22.	Yang M, Wang B, Hou W, et al. NAD+ metabolism enzyme NNMT in cancer-associated fibroblasts drives tumor progression and resistance to immunotherapy by modulating macrophages in urothelial bladder cancer. J Immunother Cancer, 2024, 12(7): e009281. doi: 10.1136/jitc-2024-009281.
23.	Parsons RB, Facey PD. Nicotinamide N-methyltransferase: an emerging protagonist in cancer macro(r)evolution. Biomolecules, 2021, 11(10): 1418. doi: 10.3390/biom11101418.
24.	Wang X, Zhao H, Luo X, et al. NNMT switches the proangiogenic phenotype of cancer-associated fibroblasts via epigenetically regulating ETS2/VEGFA axis. Oncogene, 2024, 43(35): 2647-2660.
25.	Zhao H, Li R, Chen Y, et al. Stromal nicotinamide N-methyltransferase orchestrates the crosstalk between fibroblasts and tumour cells in oral squamous cell carcinoma: evidence from patient-derived assembled organoids. Oncogene, 2023, 42(15): 1166-1180.
26.	Kocinaj A, Chaudhury T, Uddin MS, et al. High expression of nicotinamide N-methyltransferase in patients with sporadic Alzheimer’s disease. Mol Neurobiol, 2021, 58(4): 1769-1781.
27.	Jabbari P, Ardakany MR, Ebrahimi S, et al. Nicotinamide N-methyl transferase and cancer-associated thrombosis: insights to prevention and management. Epigenomics, 2023, 15(6): 385-395.
28.	Sperber H, Mathieu J, Wang Y, et al. The metabolome regulates the epigenetic landscape during naive-to-primed human embryonic stem cell transition. Nat Cell Biol, 2015, 17(12): 1523-1535.
29.	Sun WD, Zhu XJ, Li JJ, et al. Nicotinamide N-methyltransferase (NNMT): a novel therapeutic target for metabolic syndrome. Front Pharmacol, 2024, 15: 1410479. doi: 10.3389/fphar.2024.1410479.
30.	Zhao L, Liu Y, Zhang S, et al. Impacts and mechanisms of metabolic reprogramming of tumor microenvironment for immunotherapy in gastric cancer. Cell Death Dis, 2022, 13(4): 378. doi: 10.1038/s41419-022-04821-w.
31.	Lu J, Gui W, Tang S, et al. Nicotinamide N-methyltransferase (NNMT) is involved in gastric adenocarcinoma immune infiltration by driving amino acid metabolism. Nutr Cancer, 2024, 76(8): 745-759.
32.	Zhang YE, Stuelten CH. Alternative splicing in EMT and TGF-β signaling during cancer progression. Semin Cancer Biol, 2024, 101: 1-11.
33.	Chi M, Liu J, Mei C, et al. TEAD4 functions as a prognostic biomarker and triggers EMT via PI3K/AKT pathway in bladder cancer. J Exp Clin Cancer Res, 2022, 41(1): 175. doi: 10.1186/s13046-022-02377-3.
34.	Palanichamy K, Kanji S, Gordon N, et al. NNMT silencing activates tumor suppressor PP2A, inactivates oncogenic STKs, and inhibits tumor forming ability. Clin Cancer Res, 2017, 23(9): 2325-2334.
35.	Liu W, Gou H, Wang X, et al. TTPAL promotes gastric tumorigenesis by directly targeting NNMT to activate PI3K/AKT signaling. Oncogene, 2021, 40(49): 6666-6679.
36.	Yu X, Zhao H, Cao Z. The m6A methyltransferase METTL3 aggravates the progression of nasopharyngeal carcinoma through inducing EMT by m6A-modified Snail mRNA. Minerva Med, 2022, 113(2): 309-314.
37.	Liang L, Zeng M, Pan H, et al. Nicotinamide N-methyltransferase promotes epithelial-mesenchymal transition in gastric cancer cells by activating transforming growth factor-β1 expression. Oncol Lett, 2018, 15(4): 4592-4598.
38.	Christodoulidis G, Koumarelas KE, Kouliou MN, et al. Gastric cancer in the era of epigenetics. Int J Mol Sci, 2024, 25(6): 3381. doi: 10.3390/ijms25063381.
39.	Wang W, Yang C, Wang T, et al. Complex roles of nicotinamide N-methyltransferase in cancer progression. Cell Death Dis, 2022, 13(3): 267. doi: 10.1038/s41419-022-04713-z.
40.	Cortés-Guiral D, Hübner M, Alyami M, et al. Primary and metastatic peritoneal surface malignancies. Nat Rev Dis Primers, 2021, 7(1): 91. doi: 10.1038/s41572-021-00326-6.
41.	Wang Y, Zhou X, Lei Y, et al. NNMT contributes to high metastasis of triple negative breast cancer by enhancing PP2A/MEK/ERK/c-Jun/ABCA1 pathway mediated membrane fluidity. Cancer Lett, 2022, 547: 215884. doi: 10.1016/j.canlet.2022.215884.
42.	Reustle A, Menig LS, Leuthold P, et al. Nicotinamide-N-methyltransferase is a promising metabolic drug target for primary and metastatic clear cell renal cell carcinoma. Clin Transl Med, 2022, 12(6): e883. doi: 10.1002/ctm2.883.
43.	Zhu AK, Shan YQ, Zhang J, et al. Exosomal NNMT from peritoneum lavage fluid promotes peritoneal metastasis in gastric cancer. Kaohsiung J Med Sci, 2021, 37(4): 305-313.
44.	Ueno M, Sugiyama H, Li F, et al. A supramolecular biosensor for rapid and high-throughput quantification of a disease-associated niacin metabolite. Anal Chem, 2024, 96(36): 14499-14507.
45.	Satoh T, Bang YJ, Gotovkin EA, et al. Quality of life in the trastuzumab for gastric cancer trial. Oncologist, 2014, 19(7): 712-719.

1. 李茁钰, 刘凯, 张维汉, 等. 全球及中国胃癌的流行病学特点及趋势: 2018–2022《全球癌症统计报告》解读. 中国普外基础与临床杂志, 2024, 31(10): 1236-1245.
2. 姚一菲, 孙可欣, 郑荣寿. 《2022全球癌症统计报告》解读: 中国与全球对比. 中国普外基础与临床杂志, 2024, 31(7): 769-780.
3. Wu C, Liu Y, Liu W, et al. NNMT-DNMT1 axis is essential for maintaining cancer cell sensitivity to oxidative phosphorylation inhibition. Adv Sci (Weinh), 2022, 10(1): e2202642. doi: 10.1002/advs.202202642.
4. Ma Y, Huang X, Wang Y, et al. NNMT/1-MNA promote cell-cycle progression of breast cancer by targeting UBC12/cullin-1-mediated degradation of P27 proteins. Adv Sci (Weinh), 2024, 11(9): e2305907. doi: 10.1002/advs.202305907.
5. Alston TA, Abeles RH. Substrate specificity of nicotinamide methyltransferase isolated from porcine liver. Arch Biochem Biophys, 1988, 260(2): 601-608.
6. Barrows RD, Jeffries DE, Vishe M, et al. Potent uncompetitive inhibitors of nicotinamide N-methyltransferase (NNMT) as In Vivo Chemical Probes. J Med Chem, 2022, 65(21): 14642-14654.
7. Perez MF, Sarkies P. Histone methyltransferase activity affects metabolism in human cells independently of transcriptional regulation. PLoS Biol, 2023, 21(10): e3002354. doi: 10.1371/journal.pbio.3002354.
8. Davalieva K, Kiprijanovska S, Ivanovski O, et al. Proteomics profiling of bladder cancer tissues from early to advanced stages reveals NNMT and GALK1 as biomarkers for early detection and prognosis of BCa. Int J Mol Sci, 2023, 24(19): 14938. doi:10.3390/ijms241914938.
9. Nguyen TTM, Nguyen TH, Kim HS, et al. GPX8 regulates clear cell renal cell carcinoma tumorigenesis through promoting lipogenesis by NNMT. J Exp Clin Cancer Res, 2023, 42(1): 42. doi: 10.1186/s13046-023-02607-2.
10. Campagna R, Salvolini E, Pompei V, et al. Nicotinamide N-methyltransferase gene silencing enhances chemosensitivity of melanoma cell lines. Pigment Cell Melanoma Res, 2021, 34(6): 1039-1048.
11. Wang J, Liu X, Huang Y, et al. Targeting nicotinamide N-methyltransferase overcomes resistance to EGFR-TKI in non-small cell lung cancer cells. Cell Death Discov, 2022, 8(1): 170. doi: 10.1038/s41420-022-00966-x.
12. Huang Q, Chen H, Yin D, et al. Multi-omics analysis reveals NNMT as a master metabolic regulator of metastasis in esophageal squamous cell carcinoma. NPJ Precis Oncol, 2024, 8(1): 24. doi: 10.1038/s41698-024-00509-w.
13. Eckert MA, Coscia F, Chryplewicz A, et al. Proteomics reveals NNMT as a master metabolic regulator of cancer-associated fibroblasts. Nature, 2019, 569(7758): 723-728.
14. Yu X, Zhang N, Wu J, et al. Predictive value of adipokines for the severity of acute pancreatitis: a meta-analysis. BMC Gastroenterol, 2024, 24(1): 32. doi: 10.1186/s12876-024-03126-w.
15. Wang Z, Wang Q, Chen C, et al. NNMT enriches for AQP5⁺ cancer stem cells to drive malignant progression in early gastric cardia adenocarcinoma. Gut, 2023, 73(1): 63-77.
16. Chen C, Wang X, Huang X, et al. Nicotinamide N-methyltransferase: a potential biomarker for worse prognosis in gastric carcinoma. Am J Cancer Res, 2016, 6(3): 649-663.
17. 田恒金, 汪非凡, 高培垚, 等. 自噬在胃癌干细胞中的作用及研究进展. 中国现代医生, 2024, 62(6): 120-123.
18. Cui Y, Zhang L, Wang W, et al. Downregulation of nicotinamide N-methyltransferase inhibits migration and epithelial-mesenchymal transition of esophageal squamous cell carcinoma via Wnt/β-catenin pathway. Mol Cell Biochem, 2019, 460(1-2): 93-103.
19. Uribe-Etxebarria V, Pineda JR, García-Gallastegi P, et al. Notch and Wnt signaling modulation to enhance DPSC stemness and therapeutic potential. Int J Mol Sci, 2023, 24(8): 7389. doi: 10.3390/ijms24087389.
20. Tan SH, Swathi Y, Tan S, et al. AQP5 enriches for stem cells and cancer origins in the distal stomach. Nature, 2020, 578(7795): 437-443.
21. Koushyar S, Powell AG, Vincan E, et al. Targeting Wnt signaling for the treatment of gastric cancer. Int J Mol Sci, 2020, 21(11): 3927. doi: 10.3390/ijms21113927.
22. Yang M, Wang B, Hou W, et al. NAD+ metabolism enzyme NNMT in cancer-associated fibroblasts drives tumor progression and resistance to immunotherapy by modulating macrophages in urothelial bladder cancer. J Immunother Cancer, 2024, 12(7): e009281. doi: 10.1136/jitc-2024-009281.
23. Parsons RB, Facey PD. Nicotinamide N-methyltransferase: an emerging protagonist in cancer macro(r)evolution. Biomolecules, 2021, 11(10): 1418. doi: 10.3390/biom11101418.
24. Wang X, Zhao H, Luo X, et al. NNMT switches the proangiogenic phenotype of cancer-associated fibroblasts via epigenetically regulating ETS2/VEGFA axis. Oncogene, 2024, 43(35): 2647-2660.
25. Zhao H, Li R, Chen Y, et al. Stromal nicotinamide N-methyltransferase orchestrates the crosstalk between fibroblasts and tumour cells in oral squamous cell carcinoma: evidence from patient-derived assembled organoids. Oncogene, 2023, 42(15): 1166-1180.
26. Kocinaj A, Chaudhury T, Uddin MS, et al. High expression of nicotinamide N-methyltransferase in patients with sporadic Alzheimer’s disease. Mol Neurobiol, 2021, 58(4): 1769-1781.
27. Jabbari P, Ardakany MR, Ebrahimi S, et al. Nicotinamide N-methyl transferase and cancer-associated thrombosis: insights to prevention and management. Epigenomics, 2023, 15(6): 385-395.
28. Sperber H, Mathieu J, Wang Y, et al. The metabolome regulates the epigenetic landscape during naive-to-primed human embryonic stem cell transition. Nat Cell Biol, 2015, 17(12): 1523-1535.
29. Sun WD, Zhu XJ, Li JJ, et al. Nicotinamide N-methyltransferase (NNMT): a novel therapeutic target for metabolic syndrome. Front Pharmacol, 2024, 15: 1410479. doi: 10.3389/fphar.2024.1410479.
30. Zhao L, Liu Y, Zhang S, et al. Impacts and mechanisms of metabolic reprogramming of tumor microenvironment for immunotherapy in gastric cancer. Cell Death Dis, 2022, 13(4): 378. doi: 10.1038/s41419-022-04821-w.
31. Lu J, Gui W, Tang S, et al. Nicotinamide N-methyltransferase (NNMT) is involved in gastric adenocarcinoma immune infiltration by driving amino acid metabolism. Nutr Cancer, 2024, 76(8): 745-759.
32. Zhang YE, Stuelten CH. Alternative splicing in EMT and TGF-β signaling during cancer progression. Semin Cancer Biol, 2024, 101: 1-11.
33. Chi M, Liu J, Mei C, et al. TEAD4 functions as a prognostic biomarker and triggers EMT via PI3K/AKT pathway in bladder cancer. J Exp Clin Cancer Res, 2022, 41(1): 175. doi: 10.1186/s13046-022-02377-3.
34. Palanichamy K, Kanji S, Gordon N, et al. NNMT silencing activates tumor suppressor PP2A, inactivates oncogenic STKs, and inhibits tumor forming ability. Clin Cancer Res, 2017, 23(9): 2325-2334.
35. Liu W, Gou H, Wang X, et al. TTPAL promotes gastric tumorigenesis by directly targeting NNMT to activate PI3K/AKT signaling. Oncogene, 2021, 40(49): 6666-6679.
36. Yu X, Zhao H, Cao Z. The m6A methyltransferase METTL3 aggravates the progression of nasopharyngeal carcinoma through inducing EMT by m6A-modified Snail mRNA. Minerva Med, 2022, 113(2): 309-314.
37. Liang L, Zeng M, Pan H, et al. Nicotinamide N-methyltransferase promotes epithelial-mesenchymal transition in gastric cancer cells by activating transforming growth factor-β1 expression. Oncol Lett, 2018, 15(4): 4592-4598.
38. Christodoulidis G, Koumarelas KE, Kouliou MN, et al. Gastric cancer in the era of epigenetics. Int J Mol Sci, 2024, 25(6): 3381. doi: 10.3390/ijms25063381.
39. Wang W, Yang C, Wang T, et al. Complex roles of nicotinamide N-methyltransferase in cancer progression. Cell Death Dis, 2022, 13(3): 267. doi: 10.1038/s41419-022-04713-z.
40. Cortés-Guiral D, Hübner M, Alyami M, et al. Primary and metastatic peritoneal surface malignancies. Nat Rev Dis Primers, 2021, 7(1): 91. doi: 10.1038/s41572-021-00326-6.
41. Wang Y, Zhou X, Lei Y, et al. NNMT contributes to high metastasis of triple negative breast cancer by enhancing PP2A/MEK/ERK/c-Jun/ABCA1 pathway mediated membrane fluidity. Cancer Lett, 2022, 547: 215884. doi: 10.1016/j.canlet.2022.215884.
42. Reustle A, Menig LS, Leuthold P, et al. Nicotinamide-N-methyltransferase is a promising metabolic drug target for primary and metastatic clear cell renal cell carcinoma. Clin Transl Med, 2022, 12(6): e883. doi: 10.1002/ctm2.883.
43. Zhu AK, Shan YQ, Zhang J, et al. Exosomal NNMT from peritoneum lavage fluid promotes peritoneal metastasis in gastric cancer. Kaohsiung J Med Sci, 2021, 37(4): 305-313.
44. Ueno M, Sugiyama H, Li F, et al. A supramolecular biosensor for rapid and high-throughput quantification of a disease-associated niacin metabolite. Anal Chem, 2024, 96(36): 14499-14507.
45. Satoh T, Bang YJ, Gotovkin EA, et al. Quality of life in the trastuzumab for gastric cancer trial. Oncologist, 2014, 19(7): 712-719.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Latest ArticlesAdvances in the role of nicotinamide N-methyltransferase in gastric cancer and related mechanisms

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