Targeting HIF-1 alpha Function in Cancer through the Chaperone Action of NQO1: Implications of Genetic Diversity of NQO1 Salido, Eduardo Palomino Morales, Rogelio Jesús Pacheco García, Juan Luis Pey Rodríguez, Ángel Luis HIF-1alpha NQO1 Hypoxia Angiogenesis Cancer Protein: protein interactions Ligand binding Proteasomal degradation Genetic variability 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. 2022-06-14T12:42:00Z 2022-06-14T12:42:00Z 2022-05-05 info:eu-repo/semantics/article Salido, E... [et al.]. Targeting HIF-1alpha Function in Cancer through the Chaperone Action of NQO1: Implications of Genetic Diversity of NQO1. J. Pers. Med. 2022, 12, 747. [https://doi.org/10.3390/jpm12050747] http://hdl.handle.net/10481/75488 10.3390/jpm12050747 eng http://creativecommons.org/licenses/by/3.0/es/ info:eu-repo/semantics/openAccess Atribución 3.0 España MDPI