ROS-Mediated 15-Hydroxyprostaglandin Dehydrogenase Degradation via Cysteine Oxidation Promotes NAD+-Mediated Epithelial-Mesenchymal Transition. Issue 3 (15th March 2018)

• Record Type: Journal Article
• Authors: Wang, Weixuan; Hu, Yadong; Wang, Xiaofei; Wang, Qingtao; Deng, Haiteng
• Is Part Of: Cell chemical biology. Volume 25:Issue 3(2018)
• Page Start: 255
• Page End: 261.e4
• Publication Date: 2018-03-15
• Subjects: ROS -- epithelial-mesenchymal transition -- nicotinamide adenine dinucleotide -- 15-hydroxyprostaglandin dehydrogenase -- degradation; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2017.12.008
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: Nicotinamide adenine dinucleotide (NAD) levels decrease with aging as a result of aging-associated CD38 upregulation. Here, we established a cell model with decreased cellular NAD levels by overexpressing CD38 or treating cells with FK866, an inhibitor of nicotinamide phosphoribosyltransferase. We revealed that decreased NAD triggered reactive oxygen species (ROS)-mediated degradation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), which drove cells to undergo epithelial-mesenchymal transition (EMT). Moreover, we showed that oxidation of the Cys44 residue to sulfonic acid in 15-PGDH led to its degradation via non-canonical ubiquitination-proteasome and autophagy pathways. Mutation of Cys44 to alanine abolished ROS-induced 15-PGDH degradation. We demonstrated that 15-PGDH silencing promoted EMT, whereas supplementation with NAD precursors increased NAD and 15-PGDH stability, and reversed the EMT process. Taken together, these results suggest that declining NAD levels contribute to age-dependent increases in cancer incidence, and repletion of NAD precursors is beneficial for increasing 15-PGDH expression. Graphical Abstract: Highlights: Decreased NAD promoted ROS-dependent 15-PGDH degradation Proteasome- and autophagy-mediated 15-PGDH degradation depends on Cys44 oxidation Supplementation of NAD precursors upregulates 15-PGDH and reverses EMT Aging-associated decreases of cellular NAD levels may play a role in tumorigenesis Abstract : Wang et al. showed that decreased NAD promoted EMT via ROS-mediated 15-PGDH degradation. Proteasome- and autophagy-mediated 15-PGDH degradation depends on oxidation of the Cys44 residue to sulfonic acid in 15-PGDH. Supplementation of NAD precursors upregulates 15-PGDH expression.