Targeting HIF-1α Function in Cancer through the Chaperone Action of NQO1: Implications of Genetic Diversity of NQO1

Eduardo Salido, David J Timson, Isabel Betancor-Fernández, Rogelio Palomino-Morales, Ernesto Anoz-Carbonell, Juan Luis Pacheco-García, Milagros Medina, Angel L Pey

Research output: Contribution to journalArticlepeer-review

Abstract

HIF-1α is a master regulator of oxygen homeostasis involved in different stages of cancer development. Thus, HIF-1α inhibition represents an interesting target for anti-cancer therapy. It was recently shown that the HIF-1α interaction with NQO1 inhibits proteasomal degradation of the former, thus suggesting that targeting the stability and/or function of NQO1 could lead to the destabilization of HIF-1α as a therapeutic approach. Since the molecular interactions of NQO1 with HIF-1α are beginning to be unraveled, in this review we discuss: (1) Structure-function relationships of HIF-1α; (2) our current knowledge on the intracellular functions and stability of NQO1; (3) the pharmacological modulation of NQO1 by small ligands regarding function and stability; (4) the potential effects of genetic variability of NQO1 in HIF-1α levels and function; (5) the molecular determinants of NQO1 as a chaperone of many different proteins including cancer-associated factors such as HIF-1α, p53 and p73α. This knowledge is then further discussed in the context of potentially targeting the intracellular stability of HIF-1α by acting on its chaperone, NQO1. This could result in novel anti-cancer therapies, always considering that the substantial genetic variability in NQO1 would likely result in different phenotypic responses among individuals.
Original languageEnglish
Article number747
Number of pages28
JournalJournal of personalized medicine
Volume12
Issue number5
DOIs
Publication statusPublished - 5 May 2022

Keywords

  • genetic variability
  • hypoxia
  • ligand binding
  • NQO1
  • proteasomal degradation
  • protein: protein interactions
  • HIF-1α
  • cancer
  • angiogenesis

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