ROS-Mediated 15-Hydroxyprostaglandin Dehydrogenase Degradation via Cysteine Oxidation Promotes NAD+-Mediated Epithelial-Mesenchymal Transition

Cell Chem Biol. 2018 Mar 15;25(3):255-261.e4. doi: 10.1016/j.chembiol.2017.12.008. Epub 2018 Jan 4.

Abstract

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.

Keywords: 15-hydroxyprostaglandin dehydrogenase; ROS; degradation; epithelial-mesenchymal transition; nicotinamide adenine dinucleotide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-ribosyl Cyclase 1 / genetics
  • ADP-ribosyl Cyclase 1 / metabolism
  • Acrylamides / pharmacology
  • Autophagy
  • Cell Line, Tumor
  • Cell Movement
  • Cysteine / chemistry*
  • Cysteine / metabolism
  • Dinoprostone / metabolism
  • Epithelial-Mesenchymal Transition*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Hydroxyprostaglandin Dehydrogenases / antagonists & inhibitors
  • Hydroxyprostaglandin Dehydrogenases / genetics
  • Hydroxyprostaglandin Dehydrogenases / metabolism*
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Mutagenesis, Site-Directed
  • NAD / metabolism*
  • Niacin / pharmacology
  • Oxidation-Reduction
  • Piperidines / pharmacology
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Stability
  • Reactive Oxygen Species / metabolism*
  • Sulfonic Acids / chemistry

Substances

  • Acrylamides
  • Membrane Glycoproteins
  • N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide
  • Piperidines
  • Reactive Oxygen Species
  • Sulfonic Acids
  • NAD
  • Niacin
  • Hydroxyprostaglandin Dehydrogenases
  • 15-hydroxyprostaglandin dehydrogenase
  • CD38 protein, human
  • ADP-ribosyl Cyclase 1
  • Proteasome Endopeptidase Complex
  • Dinoprostone
  • Cysteine