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Published on: July 20, 2019
Nicotinamide N-Methyltransferase Remodeled Cell Metabolism and Aggravated Proinflammatory Responses by Activating
Changmei Yang1, Tianxiang Wang1, Songbiao Zhu1
1MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systematic Biology, School of Life Sciences, Tsinghua University, Beijing 100084, P. R. China.
Abstract:
Nicotinamide N-methyltransferase (NNMT) is a cytosolic methyltransferase, catalyzing N-methylation of nicotinamide (NAM) to form 1-methylnicotinamide (1-MNAM), in which S-adenosyl-l-methionine (SAM) is the methyl donor. It has been well documented that NNMT is elevated in multiple cancers and promotes tumor aggressiveness. In the present study, we investigated the effects of NNMT overexpression on cellular metabolism and proinflammatory responses. We found that NNMT overexpression reduced NAD+ and SAM levels, and activated the STAT3 signaling pathway. Consequently, STAT3 activation upregulated interleukin 1β (IL1β) and cyclooxygenase-2 (COX2), leading to prostaglandin E2 (PGE2) accumulation. On the other hand, NNMT downregulated 15-hydroxyprostaglandin dehydrogenase (15-PGDH) which catalyzes PGE2 into inactive molecules. Moreover, secretomic data indicated that NNMT promoted secretion of collagens, pro-inflammatory cytokines, and extracellular matrix proteins, confirming NNMT aggravated inflammatory responses to promote cell growth, migration, epithelial-mesenchymal transition (EMT), and chemoresistance. Taken together, we showed that NNMT played a pro-inflammatory role in cancer cells by activating the STAT3/IL1β/PGE2 axis and proposed that NNMT was a potential therapeutic target for cancer treatment.
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