Hypoxia-inducible factors and the response to hypoxic stress

Abstract

Oxygen (O(2)) is an essential nutrient that serves as a key substrate in cellular metabolism and bioenergetics. In a variety of physiological and pathological states, organisms encounter insufficient O(2) availability, or hypoxia. In order to cope with this stress, evolutionarily conserved responses are engaged. In mammals, the primary transcriptional response to hypoxic stress is mediated by the hypoxia-inducible factors (HIFs). While canonically regulated by prolyl hydroxylase domain-containing enzymes (PHDs), the HIFα subunits are intricately responsive to numerous other factors, including factor-inhibiting HIF1α (FIH1), sirtuins, and metabolites. These transcription factors function in normal tissue homeostasis and impinge on critical aspects of disease progression and recovery. Insights from basic HIF biology are being translated into pharmaceuticals targeting the HIF pathway.

Figure 1. Regulation and function of hypoxia inducible factor-α (HIFα) subunits

In the presence of oxygen and α-ketoglutarate, HIF prolyl hydroxylase domain-containing enzymes (PHDs) and Factor Inhibiting HIF (FIH1) hydroxylate and inactivate HIFα. PHD and FIH1 activity are inhibited by hypoxia and certain intracellular metabolites, including reactive oxygen species, fumarate, succinate, and potentially 2-hydroxyglutarate, resulting in HIFα stabilization. HIFα expression and/or activity is also regulated post-translationally by sirtuins and intermittent hypoxia. HIFα stabilization results in the activation of a transcriptional program with effects on metabolism, redox homoeostasis, vascular remodeling, tumorigenesis, inflammation, and other processes.

Figure 2. HIFα Control of Cell Metabolism

HIFs modulate cellular metabolism to faciliate cellular adaptation to low oxygen environments. Glucose consumption and glycolysis are promoted primarily by HIF1α, while fatty acid storage is promoted by HIF2α. Both factors inhibit mitochondrial consumption and oxidation of carbon, leading to a decreased production of ATP through oxidative phosphorylation and less reactive oxygen species (ROS) as a by-product. Instead, glycolysis makes a larger contribution to ATP synthesis in the cell. HIF2α, furthermore, inhibits ROS production through SOD2 and other targets.

Figure 3. Effects of HIF on multiple steps of cancer development

HIF is stabilized by hypoxia and other nonhypoxic stimuli in many cancers. HIF activity in cancer has been associated with 1. putative cancer ‘stem’ cell maintenance and increased expression of genes involved in 2. proliferation and survival, 3. metabolism, 4. angiogenesis, 5. recruitment of infiltrating cells such as tumor-associated macrophages and bone marrow-derived cells, and 6. tumor cell metastasis. Some examples of HIF regulated genes and oncogenic pathways are given in parentheses.

Figure 4. Macrophage and vascular responses to HIF

A, NFκB dependent regulation of HIF in macrophages. In addition to direct HIF stabilization, hypoxic inhibition of PHDs result in IKK-mediated degradation of the NFκB inhibitor IκB. Activated NFκB directly transactivates HIF1α. B, HIF activity is involved in multiple aspects of macrophage behavior via the induction of genes involved in 1. bacterial killing (NOS2, CRAMP), 2. migration and invasion (CXCR4, FN1, MCSFR), 3. cytokine production (IL1β, IL6, IL12, TNFα), and 4. metabolism (GLUT1, PGK1). C, HIF1α stabilization in endothelial cells increase 1. VEGF expression, 2. migration, and 3. proliferation, whereas HIF2α stabilization promotes 4. endothelial cell adhesion to the extracellular matrix.