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

Abstract

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.

Nicotinamide N‐methyltransferase sustains a core epigenetic program that promotes metastatic colonization in breast cancer

“…Finally, NNMT may be a potential new actionable therapeutic target for basal‐like breast cancer. Indeed, few studies have described a cytotoxic effect of putative NNMT inhibitors in clear cell renal carcinoma or in melanoma, however not in the context of metastatic disease and with limited activity in vivo (Reustle et al , 2022; Sun et al , 2022). The development of selective NNMT inhibitors potent at increasing the SAM/SAH ratio and inhibiting subsequent epigenetic programs, an accurate patient stratification based on NNMT status, and the definition of the optimal time of treatment are awaited for assessing the clinical benefit of NNMT inhibition, in order to treat patients with the most aggressive forms of breast cancer.…”

Integrative analysis of a novel super-enhancer-associated lncRNA prognostic signature and identifying LINC00945 in aggravating glioma progression

“…The formation of a tumor is usually accompanied by the formation of a tumor bed, changes in surrounding connective tissue and matrix, and, ultimately, a microenvironment suitable for the survival of tumor cells [60]. A better understanding of the TME will contribute to developing new ways to improve the TME, thereby enhancing the effect of immunotherapy, which also lays a solid foundation for the application of immunotherapy combined with other therapy in the future.…”

A Case Study of Dysfunctional Nicotinamide Metabolism in a 20-Year-Old Male

“…Similarly to NAD(H), maintaining homeostatic levels of NNMT is considered important for preserving human health. Aberrantly high expression of NNMT has been linked to the development of obesity [ 37 ], type 2 diabetes [ 38 ], various cancers [ 39 , 40 , 41 ], neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease [ 42 , 43 , 44 ], and pulmonary hypertension [ 45 ]. On the other hand, abnormally low serum levels of NNMT have been reported in bipolar mania patients [ 46 ], and higher incidents of familial schizophrenia have been correlated with lower expression of NNMT in the frontal cortex [ 47 ].…”