Nicotinamide N-Methyltransferase Remodeled Cell Metabolism and Aggravated Proinflammatory Responses by Activating STAT3/IL1β/PGE2 Pathway

作者：Changmei Yang, Tianxiang Wang, Songbiao Zhu, Zhaoyun Zong, Chengting Luo, Yujiao Zhao, Jing Liu, Ting Li, Xiaohui Liu, Chongdong Liu, Haiteng Deng · 发表于：ACS Omega · 年份：2022 · DOI：10.1021/acsomega.2c04286 · 被引用次数：15 · 研究领域：Adenosine and Purinergic Signaling、RNA modifications and cancer、Epigenetics and DNA Methylation

High Resolution Image Download MS PowerPoint Slide 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 (PGE 2 ) accumulation. On the other hand, NNMT downregulated 15-hydroxyprostaglandin dehydrogenase (15-PGDH) which catalyzes PGE 2 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/PGE 2 axis and proposed that NNMT was a potential therapeutic target for cancer treatment.