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

This research was funded by the ERDF/Spanish Ministry of Science, Innovation and Universities-State Research Agency (Grant RTI2018-096246-B-I00, to A.L.P., PID2019-110900GBI00 to M.M. and SAF2015-69796 to E.S.), Consejeriia de Economiia, Conocimiento, Empresas y Universidad, Junta de Andalucia (Grant P18-RT-2413, to A.L.P.), and the Government of AragonFEDER (Grant E35-20R to M.M.).
HIF-1 alpha is a master regulator of oxygen homeostasis involved in different stages of cancer development. Thus, HIF-1 alpha inhibition represents an interesting target for anti-cancer therapy. It was recently shown that the HIF-1 alpha 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-1 alpha as a therapeutic approach. Since the molecular interactions of NQO1 with HIF-1 alpha are beginning to be unraveled, in this review we discuss: (1) Structure-function relationships of HIF-1 alpha; (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-1 alpha levels and function; (5) the molecular determinants of NQO1 as a chaperone of many different proteins including cancer-associated factors such as HIF-1 alpha, p53 and p73 alpha. This knowledge is then further discussed in the context of potentially targeting the intracellular stability of HIF-1 alpha 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.
ERDF/Spanish Ministry of Science, Innovation and Universities-State Research Agency RTI2018-096246-B-I00 PID2019-110900GBI00 SAF2015-69796
Junta de Andalucia P18-RT-2413
Government of AragonFEDER E35-20R