Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Hypoxia-Inducible Factor-1

  • Tong Zhang
  • Zhaoji Liu
  • Zhaoyong Li
  • Huafeng Zhang
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101697


Historical Background

HIF-1, which is expressed in all metazoan organisms and serves as a transcriptional factor that responds to changes of available oxygen in the cellular environment, is a heterodimeric DNA-binding complex that is composed of two basic helix-loop-helix proteins of the PAS family: a constitutively expressed HIF-1β subunit (also known as the aryl hydrocarbon receptor nuclear translocator 1[ARNT1]) and a tightly regulated HIF-1α subunit (Wang et al. 1995). Hypoxia-inducible factor 1 (HIF-1) was first identified, biochemical purified, and molecular characterized by Gregg Semenza’s research group in the early 1990s (Semenza and Wang 1992). Both HIF-1α and HIF-1β are members of the bHLH-PAS superfamily proteins containing basic-helix-loop-helix (bHLH) and PER-ARNT-SIM (PAS) domains (Wang et al. 1995) (Fig. 1). HIF-1β subunit is a nonoxygen responsive protein, while the HIF-1α subunit is remarkably accumulated under hypoxia. Under hypoxic stress, accumulated HIF-1α is translocated into the nucleus and dimerizes with HIF-1β to form a heterodimer, which can bind to a core pentanucleotide sequence (A/GCGTG) in the hypoxia response elements (HREs) of the target genes.
Hypoxia-Inducible Factor-1, Fig. 1

Function domains of HIF subunits. All HIF subunits contain bHLH, PAS-A, PAS-B, ODD, and TAD-N domain. bHLH basic-helix-loop-helix, PAS PER-ARNT-SIM, ODD oxygen-dependent degradation, TAD-N N-terminal transactivation domain, TAD-C C-terminal transactivation domain. Please see more details in the text

Proteins that are structurally related to HIF-1α (HIF-2α, HIF-3α) and HIF-1β (ARNT2, ARNT3) have also been identified. HIF-1α and ARNT (HIF-1β) mRNA are expressed in most, if not all, human and rodent tissues. However, HIF-2α, HIF-3α, ARNT2, and ARNT3 show a more restricted pattern of expression. Of the three α-subunits, HIF-1α and HIF-2α, which have been well studied, have 48% amino acid sequence identity and similar protein structures, but are nonredundant and have distinct target genes and mechanisms of regulation. HIF-3α, whose role is not yet fully understood, has high similarity to HIF-1α and HIF-2α in the basic helix-loop-helix (bHLH) and Per-Arnt-SIM (PAS) domains but lacks the C-terminal transactivation domain (TAD-C).

In many organs, the physiological oxygen tensions are significantly lower than ambient oxygen tensions: brain (4.4%), liver (5.4%), muscle (3.8%), bone marrow (6.4%), etc. Additionally, a lot of solid tumors contain hypoxic microenvironment because of the limited diffusion of O2 from nearby vessels. As a result, cells under this physiological or pathological hypoxia developed the HIF system as a key systemic response to transactivate a large number of target genes, including those promoting angiogenesis, anaerobic metabolism, and resistance to apoptosis. Hence, in certain contexts, HIF-1 drives the initial response to hypoxia and plays essential roles in mammalian development, physiology, and disease pathogenesis.

Regulation of HIF-1 Activity

The biological activity of HIF-1 is determined by the expression and activity of the HIF-1α subunit, whose protein stability is oxygen-dependent. In normoxia, the hydroxylation of proline(P) residues (P402 and P564) in HIF-1α oxygen-dependent degradation (ODD) domain by prolyl hydroxylase domain proteins (PHDs) is required for the binding of von Hippel-Lindau (VHL) tumor-suppressor protein, which is an E3 ubiquitin-protein ligase (Fig. 2). In addition, ARD1 acetyltransferase promotes VHL binding to HIF-1 by acetylating the lysine (K) residue 532 in HIF-1α. On the other hand, FIH (factor-inhibiting-HIF-1) promotes the hydroxylation of asparagine (N) residue 803 in HIF-1α, which blocks the binding of p300 and CBP (CREB binding protein) to HIF-1α and therefore inhibits HIF-1-mediated gene transcription. Thus, a subset of genes regulated by HIF-1 appears to be sensitive to O2-dependent regulation under hypoxic conditions. VHL cannot bind to HIF-1α whose proline residues have not been prolyl-hydroxylated, resulting in a decreased degradation rate of HIF-1α. Because activation of PHDs needs oxygen as direct substrate, they are regarded as “oxygen sensors” reacting to oxygen concentration and HIF-1 regulatory response. At the same time, PHDs activation is also dependent on α-ketoglutarate (α-KG) that acts as a substrate of PHDs. Because PHDs have a catalytic Fe(II) center, iron can function as a PHD cofactor to activate PHDs and promote HIF-1α degradation. Studies have shown that in moderate hypoxia(1.5% O2), the generation of cellular reactive oxygen species (ROS) , which inhibits PHD activity and HIF-1α degradation by changing the levels of Fe(II) or Krebs cycle intermediates, can be stimulated in mitochondria. These findings suggest that mitochondria sense O2 deprivation and produce ROS to regulate PHD activity.
Hypoxia-Inducible Factor-1, Fig. 2

Regulation of HIF-1 activity. PHD catalyzes the hydroxylation of proline (P) residues (P402 and P564) and ARD1 acetyltransferase acetylates the lysine (K) residue 532 in HIF-1α, both of which promote VHL binding to HIF-1α. FIH promotes the hydroxylation of asparagine (N) residue 803 in HIF-1α, which blocks the binding of p300 and CBP to HIF-1α and inhibits HIF-1-mediated gene transcription. PHD prolyl hydroxylase domain protein, VHL von Hippel-Lindau, FIH factor-inhibiting-HIF-1, CBP: CREB binding protein

The synthesis of HIF-1α is also regulated by O2-independent mechanisms, involving many oncogenes and tumor suppressors (Majmundar et al. 2010). HIF-1α protein expression is regulated by the phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways. Firstly, growth factors activate the PI3K through binding to a receptor tyrosine kinase. Next, PI3K activates the downstream serine/threonine kinases AKT and mammalian target of rapamycin (mTOR). Meanwhile, in the MAPK pathway, MAP/ERK kinase (MEK) activates the extracellular-signal-regulated kinase (ERK). ERK, in turn, activates MNK. MNK and mTOR simultaneously promote HIF-1α translation through phosphorylating p70 S6 kinase (S6K). The posttranslational modifications of HIF-1α are also regulated by PHD/VHL-independent mechanism. It has been identified that the receptor of activated protein kinase C (RACK1) competes with heat shock protein (HSP90) for binding to HIF-1α, promoting PHD/VHL-independent proteasomal degradation of HIF-1α (Liu et al. 2007). HIF-1 expression is also regulated by noncoding RNAs. For example, miR-107, a microRNA expressed in human colon cancer and upregulated by p53, suppresses the expression of HIF-1β.

Being a master regulator of cellular response to hypoxic stress, HIF1 is extensively involved in many physiological and pathological processes, such as cerebrovascular disease, inflammation, Parkinson’s disease, and angiogenesis. Nevertheless, here, we focus on its function in cancer development.

HIF-1 and Cancer Metabolism

Reduced O2 availability has profound effects on cellular metabolism, especially in cancer. The largest functional group of genes regulated by HIF-1 is related to glucose metabolism, including glucose transporters (GLUT1 and GLUT3) and glycolytic enzymes (ALDOA, ENO1, GAPDH, HK1, HK2, PFKL, PGK1, PKM2, and LDHA) (Semenza 2012) (Fig. 3). In hypoxia, cells tend to absorb more glucose and undergo glycolysis instead of oxidative phosphorylation in mitochondria. HIF-1 can increase the glucose uptake by inducing expression of GLUT1 and GLUT3. Another important enzyme regulated by HIF-1 is LDHA, which can promote the conversion of pyruvate to lactate and is required for recycling the cytosolic NAD+ necessary for further glycolysis. The generated lactate can be removed from the cell through MCT1 and MCT4 transporters which are also regulated by HIF-1. Moreover, HIF-1α utilizes glucose as sources for both energy as well as building blocks for RNA or DNA synthesis. It has been recently reported that HIF-1α can influence the pentose phosphate pathway through regulation of transketolase, which is critical for leukemia cell growth and survival. Besides, the mitochondrial enzyme SHMT2, which is critical for maintaining NADPH production and redox balance to promote tumor proliferation, is also regulated by HIF-1.
Hypoxia-Inducible Factor-1, Fig. 3

HIF-1 regulates cancer metabolism. Through regulating genes’ expression, HIF-1 plays important roles in glucose metabolism, regulation of mitochondrial respiration, serine metabolism, and lipid metabolism. Genes marked with red color are upregulated by HIF-1, while genes marked with blue color are downregulated by HIF-1

In order to adapt to the oxygen consumption under hypoxia, cells have to adjust their mitochondria activity, because the deficiency of oxygen will increase the level of mitochondrial ROS, leading to apoptotic cell death (Simon 2006). HIF-1 regulates the mitochondrial activity through different mechanisms. First, it was showed that PDK1 is a direct transcriptional target of HIF-1 (Kim et al. 2006). PDK1 can phosphorylate and inactivate PDH, which converts pyruvate to acetyl-CoA, thereby decreasing acetyl-CoA entry into the TCA cycle. Moreover, HIF-1 downregulates mitochondria activity by activating the expression of BNIP3 and BNIP3L, which triggers selective mitochondrial autophagy, resulting in a decrease in mitochondrial mass and O2 consumption. On the other hand, HIF-1 reduces mitochondrial biogenesis through upregulating MXI-1, which attenuates PGC-1β-regulated mitochondrial biogenesis by inhibiting c-Myc oncogene (Zhang et al. 2007). More importantly, HIF-1 fine-tunes mitochondrial metabolism under hypoxia by regulating the subunits conversion of cytochrome c oxidase 4 (COX 4). Under hypoxia, HIF-1 regulates COX4 subunit expression by activating transcription of the genes encoding COX4-2 and LON, a mitochondrial protease that is required for COX4-1 degradation. HIF1 can optimize the efficiency of respiration by regulating COX4 subunit switch. Furthermore, mitochondrial complexes on inner membrane play important roles in regulating respiration. Therefore, iron-sulfur clusters, as an important part of complexes, are critical for respiration. The hypoxia-induced miR-210 directly represses the expression of ISCU1/2 (iron-sulfur cluster assembly proteins), which downregulates iron-sulfur cluster biogenesis. By repressing ISCU1/2 during hypoxia, miR-210 decreases the activity of Complex I and disrupts mitochondrial respiration. Overall, HIF-1 mediates adaptive responses to hypoxia by reducing ROS levels through the regulation of mitochondrial oxidative metabolism.

Besides the established function in glucose metabolism, HIF-1 also plays important roles in lipid metabolism. It has been reported that HIF-1 can regulate the expression of fatty acid synthase (FASN) and lipin1 (LPIN1). FASN gene, which is the major enzyme for lipogenesis and catalyzes the combination of acetyl-CoA and malonyl-CoA to produce palmitic acid, is upregulated by hypoxia through induction of the SREBP-1 gene by HIF-1. Meanwhile, HIF-1 can promote transcription of lipin1, which catalyzes the penultimate step in triglyceride biosynthesis, leading to accumulation of triglycerides and lipid droplets. In cardiac myocytes, hypoxia was reported to diminish FAO (fatty acids oxidation), and in cancer cells, it was found that HIF-1 suppresses FAO by inhibiting MCAD and LCAD (the medium- and long-chain acyl-CoA dehydrogenases) expression, two enzymes belonging to the acyl-CoA dehydrogenase family that are rate-limiting enzymes in fatty acid β-oxidation, and HIF-1-mediated FAO suppression promotes cancer proliferation partly by reducing ROS as well as by regulating cell proliferation signaling PTEN pathway (Huang et al. 2014).

HIF-1 and Cancer Metastasis

Tumor metastasis is responsible for more than 90% of all cancer patients’ death and is associated with poor survival because it is a complicated and dynamic process. HIF-1 influences multiple steps within the metastatic cascade, including EMT; invasion; and intravasation, extravasation, and metastatic niche formation (Fig. 4). Epithelial-mesenchymal transition (EMT) is defined by changes of cell morphology as the possible first step in the process of metastasis (Chaffer and Weinberg 2011). HIF-1 inhibits the expression of E-cadherin that contributes to epithelial cell-cell adhesion and tissue architecture by regulating the transcription factors such as SNAIL1, SNAIL2, TCF3, TWIST, ZEB1, and ZEB2 (Jiang et al. 2011). Low expression of E-cadherin is frequently observed in metastatic tumors including breast cancer. Next, to invade the surrounding tissues and infiltrate into vessels, cancer cells must degrade the surrounding basement membrane, in which matrix metallo-proteinases (MMPs) can degrade ECM components as the zinc-dependent endopeptidases. For example, MMP-2 and MMP-9 can degrade type IV collagen, which is a major component of the basement membrane. HIF-1 can promote the expression of MMP2 and MMP9 gene. In addition to MMPs, hypoxia also induces urokinase-type plasminogen activator receptor (PLAUR) expression, which promotes cell invasion by altering interactions between integrins and the ECM. Some recent studies discovered that HIF-1α plays an important role in collagen biogenesis in breast tumors by upregulating the expression of P4HA1, P4HA2, PLOD1, and PLOD2 hydroxylases.
Hypoxia-Inducible Factor-1, Fig. 4

HIF-1 is involved in cancer metastasis. HIF-1, through regulating genes shown in the figure, influences multiple steps within the metastatic cascade, including EMT; invasion; and intravasation, extravasation, and metastatic niche formation

The extravasation of cancer cells is a rate limit step in the metastatic process. During extravasation, cancer cells must first adhere to vascular endothelial cells (ECs), disrupting the interaction between vascular ECs. It has been found that hypoxia can increase the extravasation of cancer cells, and this effect was abrogated in HIF-knockdown cells. Two important genes, L1CAM and ANGPTL4, are involved in HIF1-regulated extravasation of cancer cells under hypoxic condition. Both L1CAM and ANGPTL4 are regulated by HIF1. L1CAM is a protein involved in cell-cell adhesion via hemophilic interaction or by heterophilic interaction with neuropilin 1(NRP1), integrin, or CD24. Overexpression of L1CAM in cancer cells promotes the adhesion of cancer cells to EC monolayers and increases the number of extravasated cancer cells in lung tissue (Zhang et al. 2012). Angiopoietin-like 4 (ANGPTL4), which is highly expressed in the primary breast cancers of women with lung metastases, inhibits EC-EC interactions. Moreover, both HIF-1 and HIF-2 contribute to ANGPTL4 expression, thereby facilitating extravasation and lung metastasis. Furthermore, HIF-1-regulated SDF-1/CXCR4 signaling may also promote the adhesion of breast cancer cells to ECs in the circulatory system.

HIF-1 also contributes to the production of secretory factors involved in premetastatic niche formation. In breast cancer cells, HIF-1 induces the expression of multiple members of the lysyl oxidase (LOX) family, including LOX, LOXL2, and LOXL4 (Wong et al. 2011). These proteins modify the collagen matrix in the lung at hydroxylated lysine residues and recruit bone-marrow-derived cells (BMDCs) to promote breast cancer premetastasic niche formation. The BMDCs promote metastasis by producing chemokines that recruit tumor cells to the lung. Interestingly, LOX, LOXL2, and LOXL4 are highly expressed in different primary human breast cancers (Wong et al. 2011). Therefore, a monoclonal antibody or small molecule inhibitor directed against LOX might be useful for breast cancer therapy. Another important mechanism is about tumor-lymphatic vessel cross-talk, leading to the formation of premetastatic niche. Lymphatic endothelial cells (LECs) are a specialized endothelium and promote lymph metastases by recruiting tumor cells to the lymphatic vessels. HIF-1 can promote VEGF expression in LECs. Furthermore, a hot topic is about whether HIF-1 signaling can promote formation of the premetastatic niche by regulation of exosomes. Studies have demonstrated that hypoxia influences exosome cargo content and promotes angiogenesis. There are also other mechanisms involved in tumor metastasis; for example, hypoxia can also promote microvesicle shedding by increasing the small guanosine triphosphatase RAB22A.

HIF-1 and Immunity

Recent studies have highlighted the importance of HIF-1 signaling in regulating immune responses, including both innate and adaptive immunity. In innate immunity, HIF-1 can influence inflammation, infection, and metabolism. (1) In regulation of inflammation, mice with HIF-1α myeloid-specific deletion showed impaired inflammatory responses. HIF-1α not only increases macrophage aggregation, invasion, and motility but also induces neutrophil survival through regulating NF-κB. HIF-1α also drives the expression of proinflammatory cytokines (TNF-α, IL-6). As a result, HIF-1 inhibition could be a potential strategy for relieving excessive inflammatory responses. (2) Since bacterial infection often leads to a hypoxic microenvironment, it is interesting to study the relationships of infection and hypoxic response. It has been reported that HIF-1α promotes granule protease production, releases nitric oxide (NO) and TNF-α, thus enhancing antimicrobial activity. (3). Myeloid cell function is broadly regulated by metabolic changes (Haschemi et al. 2012). To fight against pathogens or cancer, HIF-1α increases glycolysis and limits oxidative phosphorylation through regulating key glycolytic enzymes and PDK1 in myeloid cells.

In adaptive immunity, hypoxia and HIF-1 also play important roles, especially in T cell differentiation and function. With respect to T cell differentiation, HIF-1 regulates the balance between regulatory T cell (Treg) and Th17 differentiation. HIF-1α activates RORγt transcription and forms complexes with RORγt and P300 to activate the IL-17 gene expression during Th17 development. On the other hand, HIF-1 inhibits Treg differentiation by associating with Foxp3, leading to its proteasomal degradation (Dang et al. 2011). Lack of HIF-1α in T cells reduces the expression of glycolytic molecules and the differentiation of Th17 cells and Treg cells, which demonstrates that HIF-1 controls T cell lineage by regulating cellular metabolism. HIF-1α also regulates many molecules associated with CD8+ T cells function. For example, HIF-1α promotes the expression of important cytolytic molecules (granzyme B, perforin) and alters migration and chemokine receptor expression (Doedens et al. 2013). Therefore, HIF-1 activity in CD8+ T cells may promote pathogen clearance or diminish tumor burden.

Tumor immunology is emerging as a hot field for investigation, and HIF-1 pathway plays important roles in the regulation of tumor immunology (Fig. 5). For example, in innate tumor immunity regulation, HIF-1 contributes to the recruitment of bone-marrow-derived myeloid cells (BMDCs), which are associated with tumor immune escape, new vessel formation, and metastasis. There are two mechanisms that regulate BMDCs in hypoxic areas of tumors. First, a number of chemokines have been involved in the recruitment of bone-marrow-derived myeloid cells from the bloodstream. Therein, HIF-1α was involved in CCR5 and CCL5 regulation under hypoxia, and CCR5-CCL5 interaction promotes cancer cell migration. HIF-1α also increases the secretion of cytokines in tumor cells, mainly VEGF, which functions as a chemoattractant for myeloid cells. In particular, HIF-1 can recruit BMDC to stimulate angiogenesis by inducing SDF1α. When SDF1α decreases, fewer BMDCs are recruited to the tumors, and MMP-9 and VEGF expressions are downregulated. Importantly, macrophage infiltrating the tumor, namely tumor-associated macrophages (TAMs), was reported to correlate with poor prognosis in many human cancers. HIF-1 induces Semaphorin 3A (Sema3A) as an attractant for TAMs by triggering VEGF receptor 1 phosphorylation through Neuropilin-1 (Nrp1) and PlexinA1/PlexinA4 (Casazza et al. 2013). Deletion of Nrp1 in macrophages prevents TAM infiltration in hypoxic regions, which abates their immunosuppressive function. Myeloid-derived suppressor cells (MDSCs) are important part of the immune-suppressive network in cancer. The tumor MDSC suppresses both antigen-specific and nonspecific T cell activity. HIF-1 can alter the function of MDSC and redirect their differentiation toward tumor-associated macrophages, which upregulates NO production and arginase activity.
Hypoxia-Inducible Factor-1, Fig. 5

HIF-1 and cancer immunity. In innate immunity, HIF1, through regulating chemokines and cytokines, recruits BMDCs to promote tumor immune escape, new vessel formation, and metastasis. In adaptive immunity, HIF1 not only promotes immune escape by regulating CTLA-4 and PD-L1 but also enhances tumor tolerance and angiogenesis through regulating CCL28. BMDCs bone-marrow-derived myeloid cells, TAMs tumor-associated macrophages

In regard to adaptive tumor immunity, on one hand, CD4+ Th1 cells and CD8+ cytotoxic lymphocytes have been linked to a better prognosis in cancer patients. On the other hand, Treg cells can protect the host from autoimmunity by inhibiting self-reactive T cells. HIF-1 signaling contributes to tumoral immune escape from cytotoxic T lymphocytes (CTL) (Noman et al. 2009). Programmed cell death 1 (PD-1) and CTLA-4 act as coinhibitory receptors on activated T cells. PD-L1, as the ligand of PD-1, presents in tumor cell surface. HIF-1α not only promotes CTLA-4 expression in CD8+ T cells but also increases PD-L1 expression to promote immune escape (Doedens et al. 2013; Barsoum et al. 2014). Therefore, blocking CTLA-4 and PD-L1 expression is a promising strategy for cancer immunotherapy in hypoxic-tumor cells. Meanwhile, HIF-1 promotes the recruitment of regulatory T (Treg) cells by inducing expression of the chemokine CC-chemokine ligand 28 (CCL28), which promotes tumor tolerance and angiogenesis.

Perspectives and Summary

Soon after HIF-1 was discovered, it has been demonstrated that this protein participates in many human disease pathophysiology, such as ischemic cardiovascular disorders, pulmonary hypertension, and pregnancy disorders, especially in cancer which is the most intensively investigated. Interest in the role of hypoxia-inducible factor 1 (HIF-1) in cancer biology has grown exponentially in the past three decades. HIF-1 plays key roles in many crucial aspects of cancer cell biology including angiogenesis, metastasis, metabolism, and immunity. Traditionally, HIF-1 functions in cells via genetically changing the expression of target genes. However, more comprehensive studies have shed light on mechanisms underlying epigenetics (such as functional noncoding RNAs, histone protein modifications, and DNA methylation).

Clinical data indicates that HIF-1 high expression is associated with increased risk of cancer patient mortality. Thus, while intensive mechanistic studies are under way, HIF-1 targeted anticancer therapy has emerged as a new therapeutic approach for clinical application. Remarkably, several inhibitors (Trastuzumab, Imatinib, Camptothecin) of HIF-1 have been approved for human diseases (Semenza 2003), and screens are underway to identify novel small-molecule inhibitors of HIF-1 and test their efficacy as anticancer agents. Nowadays, with cancer immunotherapy emerging as a promising strategy for cancer patient treatment, novel strategies targeting HIF-1 in combination with current immunotherapy would probably provide more universal and effective therapeutic strategies, especially in the case of solid tumors.


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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Tong Zhang
    • 1
  • Zhaoji Liu
    • 1
  • Zhaoyong Li
    • 1
  • Huafeng Zhang
    • 1
  1. 1.Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Innate Immunity and Chronic DiseaseInnovation Center for Cell Signaling Network, and School of Life Sciences, University of Science and Technology of ChinaHefeiChina