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

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.

Effect of naturally-occurring mutations on the stability and function of cancer-associated NQO1: Comparison of experiments and computation

“…The rationale for selecting this system is three-fold: 1) human NQO1 is a multifunctional protein and mutational effects may affect these functions through complex mechanisms ( Pacheco-Garcia et al, 2022a ; Pacheco-Garcia et al, 2022b ). Therefore, contrasting experimental characterization and computational predictions can be challenging for current predictive tools and may help to improve them; 2) Altered NQO1 functionality is associated with increased risk of developing cancer and neurological disorders ( Salido et al, 2022 ). Indeed, the presence of a highly deleterious polymorphic variant in NQO1 is associated with increased cancer risk and affects multiple protein functions through allosteric effects ( Lajin and Alachkar, 2013 ; Pacheco-Garcia et al, 2022b ); 3) Over a hundred of missense variants in human NQO1 have been found in human population (i.e.…”

“…NQO1 is a multifunctional protein, displaying both enzymatic and non-enzymatic functions. As an enzyme, it catalyzes the FAD-dependent (two-electron) reduction of a large set of quinone substrates, with functions including redox maintenance of vitamins, detoxification of xenobiotics and activation of cancer pro-drugs ( Ross and Siegel, 2018 ; Beaver et al, 2019 ; Anoz-Carbonell et al, 2020 ; Salido et al, 2022 ). Among non-enzymatic functions, NQO1 may interact with proteins and RNA, controlling their stability and function ( Beaver et al, 2019 ; Asher et al, 2005 ; Ben-Nissan and Sharon, 2014 ; di Francesco et al, 2016 ; Oh et al, 2016 ).…”

Effect of naturally-occurring mutations on the stability and function of cancer-associated NQO1: comparison of experiments and computation

“…The rationale for selecting this system is three-fold: i) human NQO1 is a multifunctional protein and mutational effects may affect these functions through complex mechanisms (30,45). Therefore, contrasting experimental characterization and computational predictions can be challenging for current predictive tools and may help to improve them; ii) Altered NQO1 functionality is associated with increased risk of developing cancer and neurological disorders (13). Indeed, the presence of a highly deleterious polymorphic variant in NQO1 is associated with increased cancer risk and affects multiple functions through allosteric effects (45,46); iii) Over a hundred of missense variants in human NQO1 have been found in human population (i.e.…”

“…NQO1 is a multifunctional protein, displaying both enzymatic and non-enzymatic functions. As an enzyme, it catalyzes the FAD-dependent (twoelectron) reduction of a large set of quinone substrates, with functions including redox maintenance of vitamins, detoxification of xenobiotics and activation of cancer pro-drugs (10)(11)(12)(13). Among nonenzymatic functions, NQO1 may interact with proteins and RNA, controlling their stability and function (10,(14)(15)(16)(17).…”

Redox state and the sirtuin deacetylases are major factors that regulate the acetylation status of the stress protein NQO1

“…Some of the diverse roles of NQO1, in addition to reduction of endogenous and xenobiotic quinones, include serving as a gatekeeper of the proteasome ( Asher et al, 2005 ), regulation of microtubule acetylation ( Siegel et al, 2021 ) and binding and regulation of mRNA translation ( Castello et al, 2012 ; Di Francesco et al, 2016 ). These functions are dependent upon protein interactions between NQO1 and target molecules and have been shown to be redox-dependent ( Tsvetkov et al, 2010 ; Salido et al, 2022 ). NQO1 is a flavin adenine dinucleotide (FAD)-containing homodimeric protein that can utilize reduced pyridine nucleotides (NADH or NADPH) to catalyze the two-electron reduction of substrates.…”