The ADP-ribose reactive NUDIX hydrolase isoforms can modulate HIF-1α in cancer cells

Biochem Biophys Res Commun. 2018 Sep 26;504(1):321-327. doi: 10.1016/j.bbrc.2018.08.185. Epub 2018 Sep 4.

Abstract

The human nucleoside-diphosphate linked moiety-X (NUDIX) hydrolases that utilize ADP-ribose and NADH/NAD+ are overexpressed in cancer cells, but their roles in hypoxia inducible factor-1α (HIF-1α) regulation have not yet been revealed. Here, we showed that these NUDIX hydrolases negatively regulated HIF-1α accumulation by modulating the Ca2+ dependent AMP-activated protein kinase (AMPK) signaling pathway. In specific, knockdown of NUDT9 resulted in accumulation of free ADP-ribose that triggered Ca2+ influx mediated by transient receptor potential cation channel subfamily M member 2 and subsequent activation of Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ). In addition, AMPK activation by CaMKKβ was shown to enhance HIF-1α accumulation. Our findings provide insights into the action of NUDIX hydrolases as an additional, discrete modulator of HIF-1α accumulation.

Keywords: ADP-ribose; AMPK; HIF-1α; NUDIX hydrolase; TRPM2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Diphosphate Ribose / chemistry
  • Adenylate Kinase / metabolism
  • Calcium / metabolism
  • Gene Expression Regulation, Enzymologic*
  • Gene Expression Regulation, Neoplastic*
  • HCT116 Cells
  • HeLa Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Protein Isoforms
  • Pyrophosphatases / metabolism*
  • Signal Transduction
  • TRPM Cation Channels / metabolism

Substances

  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Protein Isoforms
  • TRPM Cation Channels
  • TRPM2 protein, human
  • Adenosine Diphosphate Ribose
  • Adenylate Kinase
  • NUDT10 protein, human
  • Pyrophosphatases
  • Calcium