Hypoxia, oxidative stress, and the interplay of HIFs and NRF2 signaling in cancer

Abstract

Oxygen is crucial for life and acts as the final electron acceptor in mitochondrial energy production. Cells adapt to varying oxygen levels through intricate response systems. Hypoxia-inducible factors (HIFs), including HIF-1α and HIF-2α, orchestrate the cellular hypoxic response, activating genes to increase the oxygen supply and reduce expenditure. Under conditions of excess oxygen and resulting oxidative stress, nuclear factor erythroid 2-related factor 2 (NRF2) activates hundreds of genes for oxidant removal and adaptive cell survival. Hypoxia and oxidative stress are core hallmarks of solid tumors and activated HIFs and NRF2 play pivotal roles in tumor growth and progression. The complex interplay between hypoxia and oxidative stress within the tumor microenvironment adds another layer of intricacy to the HIF and NRF2 signaling systems. This review aimed to elucidate the dynamic changes and functions of the HIF and NRF2 signaling pathways in response to conditions of hypoxia and oxidative stress, emphasizing their implications within the tumor milieu. Additionally, this review explored the elaborate interplay between HIFs and NRF2, providing insights into the significance of these interactions for the development of novel cancer treatment strategies.

Fig. 1. HIFs and NRF2, adaptive response systems to variable oxygen availability.

[Left] In hypoxic conditions, HIFs stabilize, translocate into the nucleus, and bind to the HRE, thereby inducing the expression of their target genes. In the presence of oxygen, HIFs are continuously degraded by the canonical PHD/pVHL-mediated pathway. The regulatory mechanism of FIH-1 also contributes to the inhibition of HIF activity. [Right] NRF2 maintains cellular redox homeostasis in response to oxidative stress, which can be induced by an excess oxygen environment. ROS/electrophiles and nonelectrophiles, such as p62, can inhibit NRF2-KEAP1 interactions to activate NRF2 target gene expression. This inhibition occurs through the KEAP1 Cys modification and competition with KEAP1 for binding to NRF2. Additionally, as a KEAP1-independent regulatory pathway, NRF2 phosphorylation by GSK-3β leads to β-TrCP-mediated proteasomal degradation of NRF2.

Fig. 2. Interplay between HIFs and NRF2.

[Top] Positive associations between HIFs and NRF2. a As a direct regulatory mechanism, NRF2 binds to the ARE located in the promoter region of the HIF1A gene, inducing the expression of HIF-1α. b The NRF2 targets TRX1 and NQO1 enhance the accumulation and stabilization of HIF-1α. Carbon monoxide produced from HO-1 also contributes to HIF-1α stabilization. c Inhibition of NRF2 increases the expression levels of miR-181c-5p and miR-181a-2-3p, suppressing HIF-1α and HIF-2α levels, respectively. d NRF2 can directly bind to the oxygen-dependent degradation domain of HIF-1α and prevent the interaction of HIF-1α with PHD2. [Bottom] Negative associations between HIFs and NRF2. e Increased NRF2 levels can suppress HIF-α through reduced ROS levels. f HIF-1α can repress the expression of NRF2 and HO-1 through the elevation of BACH1, a repressive partner of NRF2. g UBXN7 is a cofactor for the ubiquitination of both HIFs by CUL2- and NRF2 via CUL3-based complexes. UBXN7 has opposing effects on HIFs and NRF2. For instance, when UBXN7 is knocked out, NRF2 levels increase while simultaneously leading to a decrease in HIF-1α levels.

Fig. 3. Cooperative effects of HIFs and NRF2 on core cancer phenotypes.

In the tumor microenvironment characterized by hypoxia and oxidative stress, HIFs, and NRF2 are aberrantly activated, promoting core cancer phenotypes, such as cancer proliferation and survival, therapeutic resistance, angiogenesis, EMT/metastasis, CSC trait acquisition, and resistance to ferroptosis. HIFs respond to both hypoxia and oxidative stress, which are likely inevitable conditions under low-oxygen conditions. In contrast, changes in NRF2 under hypoxic conditions vary in a context-dependent manner, indicating that hypoxia-associated oxidative stress does not necessarily accompany NRF2 activation.