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

Wei Sun; Yongxiang Zou; Zheng Cai; Jinxiang Huang; Xinjie Hong; Qiang Liang; Weilin Jin

doi:10.3390/cancers14143538

Cancers (Jul 2022)

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

Wei Sun,
Yongxiang Zou,
Zheng Cai,
Jinxiang Huang,
Xinjie Hong,
Qiang Liang,
Weilin Jin

Affiliations

Wei Sun: Department of Neurosurgery, Shanghai Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
Yongxiang Zou: Neurosurgery Department, The Air Force Hospital of Northern Theater PLA, Shenyang 110041, China
Zheng Cai: Department of Neurosurgery, Shanghai Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
Jinxiang Huang: Department of Neurosurgery, Shanghai Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
Xinjie Hong: Department of Neurosurgery, Shanghai Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
Qiang Liang: Department of Neurosurgery, Shanghai Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
Weilin Jin: Institute of Cancer Neuroscience, Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, The First Clinical Medical College of Lanzhou University, Lanzhou 730000, China

DOI: https://doi.org/10.3390/cancers14143538
Journal volume & issue: Vol. 14, no. 14
p. 3538

Abstract

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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.

Published in Cancers

ISSN: 2072-6694 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: https://www.mdpi.com/journal/cancers/

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