Rapid CommunicationMinireview

Molecular Responses to Hypoxia-Inducible Factor 1α and Beyond

Jason Brocato, Yana Chervona and Max Costa
Molecular Pharmacology May 2014, 85 (5) 651-657; DOI: https://doi.org/10.1124/mol.113.089623

Abstract

Cellular response to changes in oxygen tension during normal development or pathologic processes is, in part, regulated by hypoxia-inducible factor (HIF), an oxygen-sensitive transcription factor. HIF activity is primarily controlled through post-translational modifications and stabilization of HIF-1α and HIF-2α proteins and is regulated by a number of cellular pathways involving both oxygen-dependent and -independent mechanisms. Stabilization of HIF-1α activates transcription of genes that participate in key pathways in carcinogenesis, such as angiogenesis, dedifferentiation, and invasion. Since its discovery more than two decades ago, HIF-1α has become a hot topic in molecular research and has been implicated not only in disease pathology but also in prognosis. In this review, we will focus on recent insights into HIF-1α regulation, function, and gene expression. We will also discuss emerging data on the involvement of HIF in cancer prognosis and therapeutic interventions.

Introduction

Oxygen (O2) is an indispensible component of eukaryotic metabolic processes. When oxygen demand exceeds its cellular supply, cells and tissues often become hypoxic. Hypoxia is an important factor in the pathology of a number of human diseases, including cancer, diabetes, aging, and stroke/ischemia (Melvin and Rocha, 2012; Semenza, 2012). Hypoxia can also lead to the production of oxygen radicals in a variety of experimental systems via electron attack of molecular oxygen in the inactive mitochondria (Favaro et al., 2010; Kolamunne et al., 2011; Selivanov et al., 2011). The roles of these mitochondrial-generated free radicals are especially important in hypoxia signaling pathways, which have important implications for cancer, inflammation, and a variety of other diseases (Poyton et al., 2009).

Hypoxic regions can often be found in cancer tissue due to high cellular proliferation rates coupled with the development of abnormal vasculature. Solid tumors, for example, often become hypoxic because the normal tissue vasculature can only support tumor growth within a diameter of ∼2 mm (Folkman, 1971). Cellular response to changes in oxygen tension during normal development or pathologic processes is in part regulated by hypoxia-inducible factor (HIF). HIFs are DNA-binding transcription factors that mediate cellular responses to reduced oxygen availability through transcriptional activation of a multitude of genes that encode proteins needed for oxygen delivery to tissues and energy metabolism (Manalo et al., 2005; Elvidge et al., 2006). HIFs are basic helix-loop-helix-PER-ARNT-SIM proteins that form heterodimers, composed of an oxygen-liable α-subunit (HIFα) and a stable β-subunit [HIFβ, also known as aryl hydrocarbon nuclear translocator (ARNT)]. Together, these subunits bind hypoxia-responsive elements (HREs), which are similar to Enhancer box (E-box) motifs and have the consensus sequence G/ACGTG. In humans there are three distinct HIFα isoforms: HIF-1α, encoded by HIF1A; HIF-2α, encoded by EPAS1; and HIF-3α, which is expressed by multiple HIF3a splice variants (Ke and Costa, 2006). HIF-1α, HIF-2α, and HIF-3α splice variants 1–3 possess an oxygen-dependent degradation domain (ODDD) and a N-terminal transactivation domain, whereas HIF-1α and HIF-2α possess a C-terminal transactivation domain (Ke and Costa, 2006). HIF activity is primarily controlled through post-translational modifications and stabilization of HIF-1α and HIF-2α proteins. However, HIF-1α mRNA contains an internal ribosome entry site, the presence of which allows translation to be maintained under conditions that are inhibitory to cap-dependent translation, which occurs during hypoxia (Lang et al., 2002). In this review, we will focus on recent insights into HIF-1α regulation, function, and gene expression. We will also discuss emerging data on the involvement of HIF in cancer prognosis and therapeutic interventions.

Oxygen-Dependent Regulation of HIF Signaling

2-Oxoglutarate–Dependent Dioxygenases.

Under normal oxygen tension (normoxia), HIFα becomes hydroxylated on one (or both) of the two highly conserved proline residues within the ODDD domain by prolyl-hydroxylase domain (PHD)–containing enzymes. Hydroxylated HIFα is then recognized by the β-domain of von Hippel-Lindau tumor suppressor protein (pVHL) and ubiquitinated by the Elongin BC/Cul2/pVHL (E3) ubiquitin–ligase complex. The ubiquitination then marks HIFα for proteasomal degradation (Ke and Costa, 2006; Greer et al., 2012). There are three HIF-prolyl hydroxylases known in mammals, and they are encoded by separate genes: PHD1, PHD2, and PHD3 (Myllyharju and Koivunen, 2013). Like all 2-oxoglutarate–dependent dioxygenases, PHDs require oxygen for hydroxylation, as well as tricarboxylic acid cycle intermediate, 2-oxoglutarate (α-ketoglutarate), iron (Fe2+), and ascorbate as cofactors (Schofield and Zhang, 1999). When oxygen levels are low, HIFα escapes PHD hydroxylation and recognition by the pVHL ubiquitin-ligase complex and translocates into the nucleus, where it transcriptionally activates hundreds of genes involved in erythropoiesis, angiogenesis, autophagy, and energy metabolism (Kaelin and Ratcliffe, 2008). Another dioxygenase that can influence HIF activity is the factor inhibiting hypoxia-inducible factor (FIH). When oxygen is available, FIH hydroxylates a conserved asparagine residue within the C terminus trans-activation domains of HIFα, creating a steric clash and preventing binding to coactivators such as p300/CBP, thus limiting HIF transcriptional activity (Ruas et al., 2005). FIH remains active at lower oxygen concentrations as compared with PHDs and is capable of suppressing the activity of HIFα subunits that escaped proteasomal degradation under moderate hypoxia (Dayan et al., 2006).

Given that PHDs and FIHs require α-ketoglutarate as a cosubstrate, they have been reported to be inhibited by several citric acid cycle metabolic intermediates, such as fumarate and succinate, which competitively inhibit all three PHDs with similar IC50, and citrate and oxaloacetate, which competitively inhibit FIH (Koivunen et al., 2007). This inhibition of HIF hydroxylases may explain why highly vascular tumors develop in the absence of VHL mutations. Elevated levels of fumarate and succinate, in fumarate hydratase and succinate dehydrogenase–deficient tumors, were shown to inhibit all three PHDs, resulting in consequent stabilization/upregulation of HIFα and their product genes (Isaacs et al., 2005; Selak et al., 2005).

In addition to playing a vital role in tumorigenesis, FIH has been reported to be an essential regulator of metabolism and epithelial differentiation. Fih1−/− mice displayed a range of metabolic phenotypes, such as decreased adiposity, hyperventilation, and increased insulin sensitivity. When placed on a high-fat diet, these animals were also less likely to develop insulin resistance, weight gain, and hepatic steatosis (or fatty liver) (Zhang et al., 2010). FIH1 was shown to negatively regulate corneal epithelial glycogen metabolism in a HIF-1α–independent manner, and suppression of miR-31 in human corneal epithelial keratinocytes led to increased FIH1 protein levels, decreased Notch activity, and diminished differentiation (Peng et al., 2012a,b). Moreover, FIH1 expression was markedly increased in the epidermis of patients with psoriasis and in the corneal epithelium of patients with diabetic keratopathies (Peng et al., 2012a). Collectively, these data suggest that FIH may play a role in obesity and related diseases (i.e., diabetes and nonalcoholic fatty liver disease), making it a potential target of therapeutic intervention.

Glycolytic Isoenzyme Pyruvate Kinase-M2.

Another enzyme that has been recently implicated in HIF-1α regulation is pyruvate kinase (ATP: pyruvate 2-O-phosphotransferase, EC 2.7.1.40), which is the final enzyme in glycolysis. It catalyzes the transfer of a phosphate group from phosphoenolpyruvate to ADP to create pyruvate and ATP. There are several different isoenzymes of pyruvate kinase, as follows: pyruvate kinase isoenzyme type L, which is expressed in tissues with gluconeogenesis, such as liver, kidney, and intestine, and pyruvate kinase isoenzyme types M1 and M2 (Mazurek, 2011). In tumors, M2 variant is the predominant form of pyruvate kinase that is expressed, and HIF-1α has been reported to activate PKM2 transcription (Christofk et al., 2008; Luo et al., 2011). Specifically, PHD3-mediated hydroxylation of PKM2 increased the HIF-1α binding to HREs at target genes, recruitment of coactivator p300, histone acetylation, and subsequent transactivation of HIF-1 target genes (Luo et al., 2011). PHD3 knockdown inhibited PKM2 coactivator function, reduced glucose uptake and lactate production, and increased O2 consumption in cancer cells. Moreover, PKM2 hydroxylation did not appear to be affected by 1% O2, suggesting that PHD3 is still active under hypoxic conditions. PKM2-stimulated expression of HIF-1α target genes promoted the shift from oxidative phosphorylation to glycolytic metabolism and increased expression of vascular endothelial growth factor (VEGF) gene (Luo et al., 2011). PKM2, therefore, may play a more extensive role in promoting HIF-mediated cancer progression than previously thought.

Runt-Related Transcription Factors.

HIF-1α is known to be an important regulator of angiogenesis. HIF-1α regulation and stability during angiogenesis are mediated by the runt-related transcription factor (RUNX). RUNX genes (RUNX1, RUNX2, and RUNX3), also known as the acute myeloid leukemia, are developmental regulators and play a role in human cancers (Ito, 2004). All three RUNX genes appear to be involved in HIF-1α regulation and stability during angiogenesis. RUNX1 and HIF-1α proteins were demonstrated to directly interact with one another, primarily via the Runt homology domain of RUNX1, with dual effects. RUNX1 overexpression inhibited DNA-binding and transcriptional activity of HIF-1α protein with reduced expression of the HIF1-targeted gene, VEGF, whereas silencing of RUNX1 expression by specific small interfering RNA significantly increased transcriptional activity of HIF-1α protein, suggesting that RUNX1 inhibited transcription-dependent functions of HIF-1α (Peng et al., 2008). RUNX2 was reported to compete with VHL tumor suppressor protein, by directly binding to HIF-1α ODDD and significantly inhibiting the ubiquitination of HIF-1α, without changing its hydroxylation status. Moreover, overexpression of RUNX2 enhanced in vitro and in vivo angiogenesis through enhanced secretion of VEGF (Lee et al., 2012).

The effect of RUNX3 on HIF-1α stability was also recently investigated. RUNX3 overexpression was found to attenuate HIF-1α stability under normoxic and hypoxic conditions in gastric cancer cells. Under hypoxic conditions, RUNX3 was shown to regulate the stability of HIF-1α at the post-translational level. Treatments by 5-aza-2-deoxycytidine, an inhibitor of DNA methyltransferase, and by trichostatin A, a histone deacetylase inhibitor, resulted in the recovery of RUNX3 and suppression of both HIF-1α and VEGF. Furthermore, RUNX3 was shown to directly interact with the C-terminal activation domain of HIF-1α and PHD2, potentiate proline hydroxylation, and subsequently promote the degradation of HIF-1α. RUNX3 overexpression also markedly inhibited hypoxia-induced angiogenesis in vitro and in vivo (Lee et al., 2013). Ultimately, RUNX3 suppresses hypoxia-mediated angiogenesis by destabilizing HIF-1α protein via promoting its proline hydroxylation.

Oxygen-Independent Regulation of HIF Signaling

Although HIF regulation has primarily been thought to be subject to oxygen tension, multiple studies have also reported that HIF-1α can undergo oxygen-independent regulation. As noted earlier, the oxygen-dependent degradation of the HIF-1α subunit is mediated by PHDs, VHL, Elongin C/Elongin B E3 ubiquitin-ligase complex, and the proteasome. However, inhibition of heat-shock protein 90 (HSP90) was shown to lead to oxygen/PHD/VLH-independent proteasomal degradation. Receptor for the activated protein kinase C is a HIF-1α–interacting protein that competes with HSP90 for binding to HIF-1α and is required for O2-independent and HSP90 inhibitor-induced degradation of HIF-1α (Liu et al., 2007). Hypoxia-associated factor (HAF), a novel E3-ubiquitin ligase, was also reported to bind to HIF-1α, resulting in its proteasomal degradation irrespective of cellular oxygen tension (Koh et al., 2008). HAF and HIF-1α interact in vitro and in vivo through binding of HAF residues 654–800 to HIF-1α residues 296–400, and this binding is not oxygen dependent and does not require prolyl hydroxylation (Koh et al., 2008). Therefore, HAF is capable of negatively regulating HIF-1α levels under conditions in which the pVHL-E3 ligase complex is inactive, like hypoxia.

HIF-1α and Gene Expression

HIFs are the key regulators in the major transcriptional cascade involved in the cellular response to changes in oxygen tension. Recently, several groups have used chromatin immunoprecipitation coupled to next-generation high-throughput sequencing to examine the binding of HIFα subunits across the genome (Tanimoto et al., 2010; Schödel et al., 2011). Analysis of HIF-binding motifs confirmed the 5′-RCGTG-3′ (where “R” denotes a purine residue) core-binding sequence (Simon and Keith, 2008) and revealed no additional absolute sequence requirement for HIF binding (Xia et al., 2009a; Schödel et al., 2011). HIF and several other basic helix-loop-helix transcription factors bind to the E-box binding site, CACGTG. When a cytosine precedes the HIF consensus site, the E-box site is formed (Benita et al., 2009). Moreover, these analyses also revealed that the HIFs bind to ∼500 high-affinity target sites across the genome, many of which are located at considerable distances (>100 kb) away from the genes that they regulate (Tanimoto et al., 2010; Schödel et al., 2011). The Nucleosome-Seq and chromatin immunoprecipitation coupled to next-generation high-throughput sequencing analyses of histone modifications (H3K4me3, H3Ac, and H3K27me3) and binding status of RNA polymerase II revealed that the chromatin formed an open structure in regions surrounding the HIF-1α binding sites, but this event occurred prior to the actual binding of HIF-1α (Tanimoto et al., 2010). DNase I hypersensitivity also revealed that HIFs appear to be recruited to genes that are already expressed under normoxic conditions, indicating that it is unlikely that they direct the hypoxia-induced changes in the chromatin structure of target genes. Therefore, epigenetic regulation of chromatin may have a central role in defining the hypoxic response (Schödel et al., 2011). The limited concordance (40–60%) between the HIF binding sites detected in breast cancer (MCF7) and renal cell carcinoma cell lines may indicate that the range of HIF target genes may largely be determined by the underlying cell type–specific patterns of chromatin structure (Schödel et al., 2011).

HIF-1α and Jumonji Domain–Containing Histone Demethylases

Multiple groups have also reported that HIF-1α can bind to and regulate the expression of multiple Jumonji domain–containing histone demethylases. JmjC domain lysine demethylases are members of the dioxygenase superfamily of enzymes, which contain iron and are 2-oxoglutarate–dependent enzymes (Klose et al., 2006). Many of these histone demethylases have HREs in their promoters and are induced by HIF-1α (Yang et al., 2009). For example, JARID1B (KDM5B), JMJD1A (KDM3A), JMJD2B (KDM4B), and JMJD2C (KDM4C) are known to be direct HIF-1α target genes with robust HIF-1α binding to HREs in their promoters and upregulated expression under hypoxic conditions (Pollard et al., 2008; Sar et al., 2009; Krieg et al., 2010; Guo et al., 2012). Under hypoxia, cells ectopically expressing JARID1B had decreased levels of histone 3 lysine 4 methylation (Xia et al., 2009b). Furthermore, JMJD1A was shown to regulate a subset of hypoxia-induced genes, including ADM and GDF15, by maintaining a lower level of histone 3 lysine 9 dimethylation at their promoter regions. JMJD1A was also important for tumor growth in the hypoxic microenvironment of tumor xenografts (Krieg et al., 2010). In addition to upregulating the expression of certain demethylases, hypoxia can also directly inhibit their enzyme activity because they require oxygen, α-ketoglutarate, and ascorbate as cofactors to carry out their enzymatic function. Demethylases are not completely inactive during hypoxia. Their enzymatic activity is less, so an increased amount of the enzyme is needed (Chen and Costa, 2009). Moreover, in human cancer cell lines and tumors, miR-210, a robust target of HIF and master micro RNA of the hypoxia response, was found to target the mitochondrial iron-sulfur scaffold protein, downregulation of which was the major cause of formation of reactive oxygen species in hypoxia (Favaro et al., 2010). Therefore, the hypoxia-induced production of free radical oxygen species may also diminish demethylase activity by depleting ascorbate levels or oxidizing iron necessary for the demethylase activity.

HIF-1α and Cancer Prognosis

Increased expression of HIF-1α has been observed in a broad range of human cancers, often correlating with poor prognosis (Table 1). HIF-1α and VEGF status were significantly associated with tumor stage, lymph nodes, and liver metastases in patients with colorectal cancer. Patients with positive HIF-1α and VEGF tumors tended to have a poorer prognosis and shorter survival time (Cao et al., 2009). HIF-1α overexpression was also positively correlated with colorectal liver metastasis and phosphoinositide-3-kinase catalytic subunit alpha mutation status and served as an independent risk factor for malignancy recurrence after curative resection of colorectal liver metastasis (Shimomura et al., 2013). Elevated expression of HIF-1α was associated with vascular invasion and a poor prognosis for patients with hepatocellular carcinoma (Zheng et al., 2013). In patients with esophageal squamous cell carcinoma, high HIF-1α expression was also associated with lymph node metastasis, serosa infiltration, tumor stage, and overall survival time in esophageal squamous cell carcinoma patients (Chai et al., 2013). HIF-1α expression was also correlated with angiogenesis and unfavorable prognosis in bladder cancer, gastrointestinal stromal tumor of the stomach, early-stage invasive cervical cancer, pancreatic cancer, head and neck cancer, nonsmall cell lung cancer, melanoma, and breast and ovarian cancers (Birner et al., 2000; Giatromanolaki, 2001; Giatromanolaki et al., 2001, 2003; Koukourakis et al., 2002; Shibaji et al., 2003; Takahashi et al., 2003; Theodoropoulos et al., 2004; Winter et al., 2006; Klatte et al., 2007; Sun et al., 2007a; Daponte et al., 2008; Yamamoto et al., 2008). The above studies indicate that increased expression of HIF-1α proteins in tumor cells, whether induced by hypoxia or aberrant oncogenic signaling, is responsible for driving tumor growth and progression, most likely by regulating the expression of crucial target genes that are involved in carcinogenesis.

View this table:
TABLE 1

Correlation of prognosis and HIF-1α expression in human cancers

Whereas increased HIF-1α levels are often correlated with poor prognosis, some studies have shown the opposite to be true. Fillies et al. (2005) found that HIF-1α overexpression provides a better prognosis for patients with early stage squamous cell carcinoma of the oral floor. In a study by Lidgren et al. (2006), high HIF-1α levels in renal cell carcinoma were associated with a better prognosis.

The controversy regarding HIF-1α levels and prognosis is best illustrated in a study by Vleugel et al. (2005). The group examined HIF-1α concentrations in invasive breast cancers with two overexpression patterns as follows: 1) HIF-1α overexpressed in perinecrotic regions, and 2) diffusely overexpressed HIF-1α. They found that the perinecrotic expression patterns were associated with the expression of hypoxia-associated genes carbonic anhydrase IX (CAIX) and glucose transporter 1 (GLUT1)—and this correlated with poor prognosis. Tumors with HIF-1α diffusely expressed were not associated with CAIX and GLUT1 expression, and these patients had a better prognosis (Vleugel et al., 2005). The contradicting conclusions predicting HIF-1α’s role in cancer prognosis further emphasize the complexity of HIF’s involvement in cancer.

HIF-1α and Therapeutic Interventions

Given its wide-scoping role in the pathology of human disease, HIF-1α–targeting therapeutic agents have gained considerable traction and attention among the medical and scientific community. A number of potential cancer therapeutic agents have recently been shown to function by directly or indirectly interacting with mammalian target of rapamycin (mTOR) signaling cascade. mTOR is a serine/threonine protein kinase that regulates protein synthesis, cell growth, and cell survival and is involved in both positive and negative feedback loops with HIF-1α (Demidenko and Blagosklonny, 2011). Phosphorylation of mTOR and its downstream effectors 4E-binding protein (4E-BP)1 and p70S6K was reported to raise cellular levels of HIF-1α by stimulating its translation. Specifically, HIF-1α was shown to bind with HIF-1β and activate transcription of growth factors and cytokines that stimulated the receptor tyrosine kinase–phosphoinositide-3-kinase (PI3K)–protein kinase B (Akt) pathway, which resulted in further activation of mTOR (Finlay et al., 2012; Agani and Jiang, 2013). HIF-1α was also shown to stabilize DNA damage-inducible transcript 4 (REDD1). Once stabilized, REDD1 can bind and activate tuberous sclerosis protein 2, resulting in an indirect inactivation of mTOR (Horak et al., 2010; Kucejova et al., 2011). Below, we will discuss several drugs that inhibit mTOR and/or HIF-1α, and this information is presented in Table 2. We note in this work that this is not a comprehensive list of all HIF-1α–inhibiting drugs, and the reader is referred to reviews (Xia et al., 2012; Hu et al., 2013; Tang and Yu, 2013) for more information on this topic.

View this table:
TABLE 2

HIF-1α inhibitors and mechanisms of action

Inhibition of HIF-1α protein synthesis via suppression of the PI3K-Akt-mTOR pathway appears to be a common mode of action for a number of the recently characterized anticancer drug candidates (i.e., magnolol, sorafenib, YC-1 (5-\x{200b}[1-\x{200b}(phenylmethyl)-\x{200b}1H-\x{200b}indazol-\x{200b}3-\x{200b}yl]-\x{200b}2-\x{200b}furanmethanol), and BEZ235 {2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propionitrile}). In human bladder cancer cells, the phenolic compound magnolol was shown to suppress the PI3K-Akt-mTOR pathway and subsequently reduced HIF-1α accumulation by inhibiting hypoxia-induced reactive oxygen species and VEGFR2, two known activators of the PI3K-Akt pathway (Chen et al., 2013). Sorafenib, like magnolol, was also reported to decrease synthesis of HIF-1α but mediated its effects by decreasing phosphorylation of mTOR and its downstream effectors p70S6K and 4E-BP1 (Liu et al., 2012). YC-1 prevents HIF-1α translation by suppressing the PI3K-Akt-mTOR-4E-BP pathway. YC-1 also inhibited nuclear factor κB, a downstream target of Akt (Sun et al., 2007b). Moreover, a recent study by Karar et al. (2012) reported on the HIF-1α inhibitory effects of BEZ235, an agent that inhibits both PI3K and mTOR by interacting with their ATP-binding clefts. BEZ235 proved to be a more efficient inhibitor of HIF-1α synthesis than either a mTOR inhibitor or a PI3K inhibitor alone.

Other mTOR inhibitors, such as deferasiro and SP600125 (dibenzo[cd,g]indazol-6(2H)-one), which may be therapeutic in the treatment of cancer, function to inactivate mTOR by increasing the levels of REDD1, a HIF-1α–stabilized protein (Jin et al., 2009; Ohyashiki et al., 2009). Given the implications of HIF-1α in human cancers, it is likely that the mTOR inhibitors that function to reduce HIF-1α levels are likely to have promising treatment effects. However, further research is needed to establish mTOR inhibitors as effective chemotherapeutics.

Some other notable drugs that have shown promising results for the inhibition of HIF-1α in cancer therapy include topotecan and PX-478 [(S)-4-(2-amino-2-carboxyethyl)-N,N-bis(2-chloroethyl)aniline oxide dihydrochloride]. Topotecan is a topoisomerase I (Top I) inhibitor and has been shown to inhibit HIF-1α. Top I is a monomeric enzyme that catalyzes the conversions of the different topological states of DNA. Topotecan stabilizes Top I on DNA and induces DNA damage during replication; however, topotecan has been shown to inhibit HIF-1α in an S-phase–independent manner. Topotecan inhibits HIF-1α accumulation by preventing translation of HIF-1α mRNA, and Top I is required for this inhibition (Rapisarda et al., 2004). PX-478 is the first HIF-1α inhibitor to be used at a clinical stage for the treatment of solid tumors. The drug inhibits HIF-1α levels via a number of mechanisms, as follows: 1) decreasing HIF-1α mRNA levels, 2) preventing HIF-1α translation, and 3) preventing HIF-1α deubiquitination. The drug significantly decreased expression of the HIF-1α target genes, VEGF and GLUT-1 (Lee and Kim, 2011). Although the inhibition of HIF-1α appears to be a promising field of cancer research, only a few of the drugs have advanced past preclinical and clinical development, and further investigations are needed to establish these drugs as valid tools in chemotherapy.

Conclusion

HIF is a transcription factor that is regulated by a number of cellular pathways involving both oxygen-dependent and oxygen-independent mechanisms. Stabilized HIF-1α activates transcription of genes that participate in angiogenesis, dedifferentiation, and invasion—all of which are key pathways in carcinogenesis. Due to its large role in cancer and its association with poor prognosis, it is not surprising that HIF-1α has become an important topic in molecular research. The complex mechanisms underlying the hypoxic microenvironment of solid tumors have yet to be fully characterized, but it is certain that HIF-1α is a key mediator. Manipulating pathways and mediators, such as mTOR, that are known to regulate HIF-1α may be of therapeutic value. Future research should attempt to unearth the missing links between HIF and cancer metabolism, as well as examine the therapeutic effects of small molecular inhibitors of HIF-1α regulators.

Authorship Contributions

Wrote or contributed to the writing of the manuscript: Brocato, Chervona, Costa.

Footnotes

    • Received September 12, 2013.
    • Accepted February 25, 2014.

  • This work was supported by the National Institutes of Health National Institute of Environmental Health Sciences [Grants P30-ES000260, P42-ES010344, R01-ES014454, and R01-ES005512].

  • dx.doi.org/10.1124/mol.113.089623.

Abbreviations

4E-BP
4E-binding protein
Akt
protein kinase B
BEZ235
2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propionitrile
E3
Elongin BC/Cul2/pVHL
E-box
Enhancer box
FIH
factor inhibiting hypoxia-inducible factor
HAF
hypoxia-associated factor
HIF
hypoxia-inducible factor
HRE
hypoxia-responsive element
HSP90
heat-shock protein 90
mTOR
mammalian target of rapamycin
ODDD
oxygen-dependent degradation domain
PHD
prolyl-hydroxylase domain
PI3K
phosphoinositide-3-kinase
pVHL
von Hippel-Lindau tumor suppressor protein
PX-478
(S)-4-(2-amino-2-carboxyethyl)-N,N-bis(2-chloroethyl)aniline oxide dihydrochloride
REDD1
DNA damage-inducible transcript 4
RUNX
runt-related transcription factor
SP600125
dibenzo[cd,g]indazol-6(2H)-one
Top I
topoisomerase I
VEGF
vascular endothelial growth factor
YC-1
5-[1-(phenylmethyl)-1H-indazol-3-yl]-2-furanmethanol

References

  1. ↵
    1. Agani F and
    2. Jiang BH
    (2013) Oxygen-independent regulation of HIF-1: novel involvement of PI3K/AKT/mTOR pathway in cancer. Curr Cancer Drug Targets 13:245–251.
    OpenUrlCrossRefPubMed
  2. ↵
    1. Benita Y,
    2. Kikuchi H,
    3. Smith AD,
    4. Zhang MQ,
    5. Chung DC, and
    6. Xavier RJ
    (2009) An integrative genomics approach identifies hypoxia inducible factor-1 (HIF-1)-target genes that form the core response to hypoxia. Nucleic Acids Res 37:4587–4602.
    OpenUrlAbstract/FREE Full Text
  3. ↵
    1. Birner P,
    2. Schindl M,
    3. Obermair A,
    4. Plank C,
    5. Breitenecker G, and
    6. Oberhuber G
    (2000) Overexpression of hypoxia-inducible factor 1alpha is a marker for an unfavorable prognosis in early-stage invasive cervical cancer. Cancer Res 60:4693–4696.
    OpenUrlAbstract/FREE Full Text
  4. ↵
    1. Cao D,
    2. Hou M,
    3. Guan YS,
    4. Jiang M,
    5. Yang Y, and
    6. Gou HF
    (2009) Expression of HIF-1alpha and VEGF in colorectal cancer: association with clinical outcomes and prognostic implications. BMC Cancer 9:432.
    OpenUrlCrossRefPubMed
  5. ↵
    1. Chai DM,
    2. Bao ZQ,
    3. Hu JG,
    4. Ma L,
    5. Feng ZZ, and
    6. Tao YS
    (2013) Vasculogenic mimicry and aberrant expression of HIF-lα/E-cad are associated with worse prognosis of esophageal squamous cell carcinoma. J Huazhong Univ Sci Technolog Med Sci 33:385–391.
    OpenUrlCrossRefPubMed
  6. ↵
    1. Chen H and
    2. Costa M
    (2009) Iron- and 2-oxoglutarate-dependent dioxygenases: an emerging group of molecular targets for nickel toxicity and carcinogenicity. Biometals 22:191–196.
    OpenUrlCrossRefPubMed
  7. ↵
    1. Chen MC,
    2. Lee CF,
    3. Huang WH, and
    4. Chou TC
    (2013) Magnolol suppresses hypoxia-induced angiogenesis via inhibition of HIF-1α/VEGF signaling pathway in human bladder cancer cells. Biochem Pharmacol 85:1278–1287.
    OpenUrlCrossRefPubMed
  8. ↵
    1. Christofk HR,
    2. Vander Heiden MG,
    3. Harris MH,
    4. Ramanathan A,
    5. Gerszten RE,
    6. Wei R,
    7. Fleming MD,
    8. Schreiber SL, and
    9. Cantley LC
    (2008) The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452:230–233.
    OpenUrlCrossRefPubMed
  9. ↵
    1. Daponte A,
    2. Ioannou M,
    3. Mylonis I,
    4. Simos G,
    5. Minas M,
    6. Messinis IE, and
    7. Koukoulis G
    (2008) Prognostic significance of hypoxia-inducible factor 1 alpha(HIF-1 alpha) expression in serous ovarian cancer: an immunohistochemical study. BMC Cancer 8:335.
    OpenUrlCrossRefPubMed
  10. ↵
    1. Dayan F,
    2. Roux D,
    3. Brahimi-Horn MC,
    4. Pouyssegur J, and
    5. Mazure NM
    (2006) The oxygen sensor factor-inhibiting hypoxia-inducible factor-1 controls expression of distinct genes through the bifunctional transcriptional character of hypoxia-inducible factor-1alpha. Cancer Res 66:3688–3698.
    OpenUrlAbstract/FREE Full Text
  11. ↵
    1. Demidenko ZN and
    2. Blagosklonny MV
    (2011) The purpose of the HIF-1/PHD feedback loop: to limit mTOR-induced HIF-1α. Cell Cycle 10:1557–1562.
    OpenUrlCrossRefPubMed
  12. ↵
    1. Elvidge GP,
    2. Glenny L,
    3. Appelhoff RJ,
    4. Ratcliffe PJ,
    5. Ragoussis J, and
    6. Gleadle JM
    (2006) Concordant regulation of gene expression by hypoxia and 2-oxoglutarate-dependent dioxygenase inhibition: the role of HIF-1alpha, HIF-2alpha, and other pathways. J Biol Chem 281:15215–15226.
    OpenUrlAbstract/FREE Full Text
  13. ↵
    1. Favaro E,
    2. Ramachandran A,
    3. McCormick R,
    4. Gee H,
    5. Blancher C,
    6. Crosby M,
    7. Devlin C,
    8. Blick C,
    9. Buffa F,
    10. Li JL,
    11. et al.
    (2010) MicroRNA-210 regulates mitochondrial free radical response to hypoxia and krebs cycle in cancer cells by targeting iron sulfur cluster protein ISCU. PLoS One 5:e10345.
    OpenUrlCrossRefPubMed
  14. ↵
    1. Fillies T,
    2. Werkmeister R,
    3. van Diest PJ,
    4. Brandt B,
    5. Joos U, and
    6. Buerger H
    (2005) HIF1-alpha overexpression indicates a good prognosis in early stage squamous cell carcinomas of the oral floor. BMC Cancer 5:84.
    OpenUrlCrossRefPubMed
  15. ↵
    1. Finlay DK,
    2. Rosenzweig E,
    3. Sinclair LV,
    4. Feijoo-Carnero C,
    5. Hukelmann JL,
    6. Rolf J,
    7. Panteleyev AA,
    8. Okkenhaug K, and
    9. Cantrell DA
    (2012) PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells. J Exp Med 209:2441–2453.
    OpenUrlAbstract/FREE Full Text
  16. ↵
    1. Folkman J
    (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186.
    OpenUrlCrossRefPubMed
  17. ↵
    1. Giatromanolaki A
    (2001) Prognostic role of angiogenesis in non-small cell lung cancer. Anticancer Res 21:4373–4382.
    OpenUrlPubMed
  18. ↵
    1. Giatromanolaki A,
    2. Koukourakis MI,
    3. Sivridis E,
    4. Turley H,
    5. Talks K,
    6. Pezzella F,
    7. Gatter KC, and
    8. Harris AL
    (2001) Relation of hypoxia inducible factor 1 alpha and 2 alpha in operable non-small cell lung cancer to angiogenic/molecular profile of tumours and survival. Br J Cancer 85:881–890.
    OpenUrlCrossRefPubMed
  19. ↵
    1. Giatromanolaki A,
    2. Sivridis E,
    3. Kouskoukis C,
    4. Gatter KC,
    5. Harris AL, and
    6. Koukourakis MI
    (2003) Hypoxia-inducible factors 1alpha and 2alpha are related to vascular endothelial growth factor expression and a poorer prognosis in nodular malignant melanomas of the skin. Melanoma Res 13:493–501.
    OpenUrlCrossRefPubMed
  20. ↵
    1. Greer SN,
    2. Metcalf JL,
    3. Wang Y, and
    4. Ohh M
    (2012) The updated biology of hypoxia-inducible factor. EMBO J 31:2448–2460.
    OpenUrlAbstract/FREE Full Text
  21. ↵
    1. Guo X,
    2. Lu J,
    3. Wang Y,
    4. Gui Y,
    5. Duan X, and
    6. Cai Z
    (2012) Ascorbate antagonizes nickel ion to regulate JMJD1A expression in kidney cancer cells. Acta Biochim Biophys Sin (Shanghai) 44:330–338.
    OpenUrlAbstract/FREE Full Text
  22. ↵
    1. Horak P,
    2. Crawford AR,
    3. Vadysirisack DD,
    4. Nash ZM,
    5. DeYoung MP,
    6. Sgroi D, and
    7. Ellisen LW
    (2010) Negative feedback control of HIF-1 through REDD1-regulated ROS suppresses tumorigenesis. Proc Natl Acad Sci USA 107:4675–4680.
    OpenUrlAbstract/FREE Full Text
  23. ↵
    1. Hu Y,
    2. Liu J, and
    3. Huang H
    (2013) Recent agents targeting HIF-1α for cancer therapy. J Cell Biochem 114:498–509.
    OpenUrlCrossRefPubMed
  24. ↵
    1. Isaacs JS,
    2. Jung YJ,
    3. Mole DR,
    4. Lee S,
    5. Torres-Cabala C,
    6. Chung YL,
    7. Merino M,
    8. Trepel J,
    9. Zbar B,
    10. Toro J,
    11. et al.
    (2005) HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell 8:143–153.
    OpenUrlCrossRefPubMed
  25. ↵
    1. Ito Y
    (2004) Oncogenic potential of the RUNX gene family: ‘overview.’ Oncogene 23:4198–4208.
    OpenUrlCrossRefPubMed
  26. ↵
    1. Jin HO,
    2. Seo SK,
    3. Woo SH,
    4. Kim ES,
    5. Lee HC,
    6. Yoo DH,
    7. Choe TB,
    8. Hong SI,
    9. Kim JI, and
    10. Park IC
    (2009) SP600125 negatively regulates the mammalian target of rapamycin via ATF4-induced Redd1 expression. FEBS Lett 583:123–127.
    OpenUrlCrossRefPubMed
  27. ↵
    1. Kaelin WG Jr. and
    2. Ratcliffe PJ
    (2008) Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell 30:393–402.
    OpenUrlCrossRefPubMed
  28. ↵
    Karar J, Cerniglia GJ, Lindsten T, Koumenis C, and Maity A (2012) Dual PI3K/mTOR inhibitor NVP-BEZ235 suppresses hypoxia-inducible factor (HIF)-1alpha expression by blocking protein translation and increases cell death under hypoxia. Cancer Biol Ther 13:1102–1111.
  29. ↵
    1. Ke Q and
    2. Costa M
    (2006) Hypoxia-inducible factor-1 (HIF-1). Mol Pharmacol 70:1469–1480.
    OpenUrlAbstract/FREE Full Text
  30. ↵
    1. Klatte T,
    2. Seligson DB,
    3. Riggs SB,
    4. Leppert JT,
    5. Berkman MK,
    6. Kleid MD,
    7. Yu H,
    8. Kabbinavar FF,
    9. Pantuck AJ, and
    10. Belldegrun AS
    (2007) Hypoxia-inducible factor 1 alpha in clear cell renal cell carcinoma. Clin Cancer Res 13:7388–7393.
    OpenUrlAbstract/FREE Full Text
  31. ↵
    1. Klose RJ,
    2. Kallin EM, and
    3. Zhang Y
    (2006) JmjC-domain-containing proteins and histone demethylation. Nat Rev Genet 7:715–727.
    OpenUrlCrossRefPubMed
  32. ↵
    1. Koh MY,
    2. Darnay BG, and
    3. Powis G
    (2008) Hypoxia-associated factor, a novel E3-ubiquitin ligase, binds and ubiquitinates hypoxia-inducible factor 1alpha, leading to its oxygen-independent degradation. Mol Cell Biol 28:7081–7095.
    OpenUrlAbstract/FREE Full Text
  33. ↵
    1. Koivunen P,
    2. Hirsilä M,
    3. Remes AM,
    4. Hassinen IE,
    5. Kivirikko KI, and
    6. Myllyharju J
    (2007) Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF. J Biol Chem 282:4524–4532.
    OpenUrlAbstract/FREE Full Text
  34. ↵
    1. Kolamunne RT,
    2. Clare M, and
    3. Griffiths HR
    (2011) Mitochondrial superoxide anion radicals mediate induction of apoptosis in cardiac myoblasts exposed to chronic hypoxia. Arch Biochem Biophys 505:256–265.
    OpenUrlCrossRefPubMed
  35. ↵
    1. Koukourakis MI,
    2. Giatromanolaki A,
    3. Sivridis E,
    4. Simopoulos C,
    5. Turley H,
    6. Talks K,
    7. Gatter KC, and
    8. Harris AL
    (2002) Hypoxia-inducible factor (HIF1A and HIF2A), angiogenesis, and chemoradiotherapy outcome of squamous cell head-and-neck cancer. Int J Radiat Oncol Biol Phys 53:1192–1202.
    OpenUrlCrossRefPubMed
  36. ↵
    1. Krieg AJ,
    2. Rankin EB,
    3. Chan D,
    4. Razorenova O,
    5. Fernandez S, and
    6. Giaccia AJ
    (2010) Regulation of the histone demethylase JMJD1A by hypoxia-inducible factor 1 alpha enhances hypoxic gene expression and tumor growth. Mol Cell Biol 30:344–353.
    OpenUrlAbstract/FREE Full Text
  37. ↵
    1. Kucejova B,
    2. Peña-Llopis S,
    3. Yamasaki T,
    4. Sivanand S,
    5. Tran TA,
    6. Alexander S,
    7. Wolff NC,
    8. Lotan Y,
    9. Xie XJ,
    10. Kabbani W,
    11. et al.
    (2011) Interplay between pVHL and mTORC1 pathways in clear-cell renal cell carcinoma. Mol Cancer Res 9:1255–1265.
    OpenUrlAbstract/FREE Full Text
  38. ↵
    1. Lang KJ,
    2. Kappel A, and
    3. Goodall GJ
    (2002) Hypoxia-inducible factor-1alpha mRNA contains an internal ribosome entry site that allows efficient translation during normoxia and hypoxia. Mol Biol Cell 13:1792–1801.
    OpenUrlAbstract/FREE Full Text
  39. ↵
    1. Lee K and
    2. Kim HM
    (2011) A novel approach to cancer therapy using PX-478 as a HIF-1α inhibitor. Arch Pharm Res 34:1583–1585.
    OpenUrlCrossRefPubMed
  40. ↵
    Lee SH, Bae SC, Kim KW, and Lee YM (2013) RUNX3 inhibits hypoxia-inducible factor-1α protein stability by interacting with prolyl hydroxylases in gastric cancer cells [published ahead of print]. Oncogene DOI: 10.1038/onc.2013.76.
  41. ↵
    1. Lee SH,
    2. Che X,
    3. Jeong JH,
    4. Choi JY,
    5. Lee YJ,
    6. Lee YH,
    7. Bae SC, and
    8. Lee YM
    (2012) Runx2 protein stabilizes hypoxia-inducible factor-1α through competition with von Hippel-Lindau protein (pVHL) and stimulates angiogenesis in growth plate hypertrophic chondrocytes. J Biol Chem 287:14760–14771.
    OpenUrlAbstract/FREE Full Text
  42. ↵
    1. Lidgren A,
    2. Hedberg Y,
    3. Grankvist K,
    4. Rasmuson T,
    5. Bergh A, and
    6. Ljungberg B
    (2006) Hypoxia-inducible factor 1alpha expression in renal cell carcinoma analyzed by tissue microarray. Eur Urol 50:1272–1277.
    OpenUrlCrossRefPubMed
  43. ↵
    Liu LP, Ho RL, Chen GG, and Lai PB (2012) Sorafenib inhibits hypoxia-inducible factor-1alpha synthesis: implications for antiangiogenic activity in hepatocellular carcinoma. Clin Cancer Res 18:5662–5671.
  44. ↵
    1. Liu YV,
    2. Baek JH,
    3. Zhang H,
    4. Diez R,
    5. Cole RN, and
    6. Semenza GL
    (2007) RACK1 competes with HSP90 for binding to HIF-1alpha and is required for O(2)-independent and HSP90 inhibitor-induced degradation of HIF-1alpha. Mol Cell 25:207–217.
    OpenUrlCrossRefPubMed
  45. ↵
    1. Luo W,
    2. Hu H,
    3. Chang R,
    4. Zhong J,
    5. Knabel M,
    6. O’Meally R,
    7. Cole RN,
    8. Pandey A, and
    9. Semenza GL
    (2011) Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell 145:732–744.
    OpenUrlCrossRefPubMed
  46. ↵
    1. Manalo DJ,
    2. Rowan A,
    3. Lavoie T,
    4. Natarajan L,
    5. Kelly BD,
    6. Ye SQ,
    7. Garcia JG, and
    8. Semenza GL
    (2005) Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1. Blood 105:659–669.
    OpenUrlAbstract/FREE Full Text
  47. ↵
    1. Mazurek S
    (2011) Pyruvate kinase type M2: a key regulator of the metabolic budget system in tumor cells. Int J Biochem Cell Biol 43:969–980.
    OpenUrlCrossRefPubMed
  48. ↵
    1. Melvin A and
    2. Rocha S
    (2012) Chromatin as an oxygen sensor and active player in the hypoxia response. Cell Signal 24:35–43.
    OpenUrlCrossRefPubMed
  49. ↵
    1. Myllyharju J and
    2. Koivunen P
    (2013) Hypoxia-inducible factor prolyl 4-hydroxylases: common and specific roles. Biol Chem 394:435–448.
    OpenUrlCrossRefPubMed
  50. ↵
    1. Ohyashiki JH,
    2. Kobayashi C,
    3. Hamamura R,
    4. Okabe S,
    5. Tauchi T, and
    6. Ohyashiki K
    (2009) The oral iron chelator deferasirox represses signaling through the mTOR in myeloid leukemia cells by enhancing expression of REDD1. Cancer Sci 100:970–977.
    OpenUrlCrossRefPubMed
  51. ↵
    1. Peng H,
    2. Hamanaka RB,
    3. Katsnelson J,
    4. Hao LL,
    5. Yang W,
    6. Chandel NS, and
    7. Lavker RM
    (2012a) MicroRNA-31 targets FIH-1 to positively regulate corneal epithelial glycogen metabolism. FASEB J 26:3140–3147.
    OpenUrlAbstract/FREE Full Text
  52. ↵
    1. Peng H,
    2. Kaplan N,
    3. Hamanaka RB,
    4. Katsnelson J,
    5. Blatt H,
    6. Yang W,
    7. Hao L,
    8. Bryar PJ,
    9. Johnson RS,
    10. Getsios S,
    11. et al.
    (2012b) microRNA-31/factor-inhibiting hypoxia-inducible factor 1 nexus regulates keratinocyte differentiation. Proc Natl Acad Sci USA 109:14030–14034.
    OpenUrlAbstract/FREE Full Text
  53. ↵
    1. Peng ZG,
    2. Zhou MY,
    3. Huang Y,
    4. Qiu JH,
    5. Wang LS,
    6. Liao SH,
    7. Dong S, and
    8. Chen GQ
    (2008) Physical and functional interaction of Runt-related protein 1 with hypoxia-inducible factor-1alpha. Oncogene 27:839–847.
    OpenUrlCrossRefPubMed
  54. ↵
    1. Pollard PJ,
    2. Loenarz C,
    3. Mole DR,
    4. McDonough MA,
    5. Gleadle JM,
    6. Schofield CJ, and
    7. Ratcliffe PJ
    (2008) Regulation of Jumonji-domain-containing histone demethylases by hypoxia-inducible factor (HIF)-1alpha. Biochem J 416:387–394.
    OpenUrlAbstract/FREE Full Text
  55. ↵
    1. Poyton RO,
    2. Ball KA, and
    3. Castello PR
    (2009) Mitochondrial generation of free radicals and hypoxic signaling. Trends Endocrinol Metab 20:332–340.
    OpenUrlCrossRefPubMed
  56. ↵
    1. Rapisarda A,
    2. Uranchimeg B,
    3. Sordet O,
    4. Pommier Y,
    5. Shoemaker RH, and
    6. Melillo G
    (2004) Topoisomerase I-mediated inhibition of hypoxia-inducible factor 1: mechanism and therapeutic implications. Cancer Res 64:1475–1482.
    OpenUrlAbstract/FREE Full Text
  57. ↵
    1. Ruas JL,
    2. Poellinger L, and
    3. Pereira T
    (2005) Role of CBP in regulating HIF-1-mediated activation of transcription. J Cell Sci 118:301–311.
    OpenUrlAbstract/FREE Full Text
  58. ↵
    1. Sar A,
    2. Ponjevic D,
    3. Nguyen M,
    4. Box AH, and
    5. Demetrick DJ
    (2009) Identification and characterization of demethylase JMJD1A as a gene upregulated in the human cellular response to hypoxia. Cell Tissue Res 337:223–234.
    OpenUrlCrossRefPubMed
  59. ↵
    1. Schödel J,
    2. Oikonomopoulos S,
    3. Ragoussis J,
    4. Pugh CW,
    5. Ratcliffe PJ, and
    6. Mole DR
    (2011) High-resolution genome-wide mapping of HIF-binding sites by ChIP-seq. Blood 117:e207–e217.
    OpenUrlAbstract/FREE Full Text
  60. ↵
    1. Schofield CJ and
    2. Zhang Z
    (1999) Structural and mechanistic studies on 2-oxoglutarate-dependent oxygenases and related enzymes. Curr Opin Struct Biol 9:722–731.
    OpenUrlCrossRefPubMed
  61. ↵
    1. Selak MA,
    2. Armour SM,
    3. MacKenzie ED,
    4. Boulahbel H,
    5. Watson DG,
    6. Mansfield KD,
    7. Pan Y,
    8. Simon MC,
    9. Thompson CB, and
    10. Gottlieb E
    (2005) Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 7:77–85.
    OpenUrlCrossRefPubMed
  62. ↵
    1. Selivanov VA,
    2. Votyakova TV,
    3. Pivtoraiko VN,
    4. Zeak J,
    5. Sukhomlin T,
    6. Trucco M,
    7. Roca J, and
    8. Cascante M
    (2011) Reactive oxygen species production by forward and reverse electron fluxes in the mitochondrial respiratory chain. PLOS Comput Biol 7:e1001115.
    OpenUrlCrossRefPubMed
  63. ↵
    1. Semenza GL
    (2012) Hypoxia-inducible factors in physiology and medicine. Cell 148:399–408.
    OpenUrlCrossRefPubMed
  64. ↵
    1. Shibaji T,
    2. Nagao M,
    3. Ikeda N,
    4. Kanehiro H,
    5. Hisanaga M,
    6. Ko S,
    7. Fukumoto A, and
    8. Nakajima Y
    (2003) Prognostic significance of HIF-1 alpha overexpression in human pancreatic cancer. Anticancer Res 23:4721–4727.
    OpenUrlPubMed
  65. ↵
    Shimomura M, Hinoi T, Kuroda S, Adachi T, Kawaguchi Y, Sasada T, Takakura Y, Egi H, Okajima M, Tashiro H et al. (2013) Overexpression of hypoxia inducible factor-1 alpha is an independent risk factor for recurrence after curative resection of colorectal liver metastases. Ann Surg Oncol 20(Suppl 3):S527–S536.
  66. ↵
    1. Simon MC and
    2. Keith B
    (2008) The role of oxygen availability in embryonic development and stem cell function. Nat Rev Mol Cell Biol 9:285–296.
    OpenUrlCrossRefPubMed
  67. ↵
    1. Sun HC,
    2. Qiu ZJ,
    3. Liu J,
    4. Sun J,
    5. Jiang T,
    6. Huang KJ,
    7. Yao M, and
    8. Huang C
    (2007a) Expression of hypoxia-inducible factor-1 alpha and associated proteins in pancreatic ductal adenocarcinoma and their impact on prognosis. Int J Oncol 30:1359–1367.
    OpenUrlPubMed
  68. ↵
    1. Sun HL,
    2. Liu YN,
    3. Huang YT,
    4. Pan SL,
    5. Huang DY,
    6. Guh JH,
    7. Lee FY,
    8. Kuo SC, and
    9. Teng CM
    (2007b) YC-1 inhibits HIF-1 expression in prostate cancer cells: contribution of Akt/NF-kappaB signaling to HIF-1alpha accumulation during hypoxia. Oncogene 26:3941–3951.
    OpenUrlCrossRefPubMed
  69. ↵
    1. Takahashi R,
    2. Tanaka S,
    3. Hiyama T,
    4. Ito M,
    5. Kitadai Y,
    6. Sumii M,
    7. Haruma K, and
    8. Chayama K
    (2003) Hypoxia-inducible factor-1alpha expression and angiogenesis in gastrointestinal stromal tumor of the stomach. Oncol Rep 10:797–802.
    OpenUrlPubMed
  70. ↵
    1. Tang CM and
    2. Yu J
    (2013) Hypoxia-inducible factor-1 as a therapeutic target in cancer. J Gastroenterol Hepatol 28:401–405.
    OpenUrlCrossRefPubMed
  71. ↵
    1. Tanimoto K,
    2. Tsuchihara K,
    3. Kanai A,
    4. Arauchi T,
    5. Esumi H,
    6. Suzuki Y, and
    7. Sugano S
    (2010) Genome-wide identification and annotation of HIF-1α binding sites in two cell lines using massively parallel sequencing. Hugo J 4:35–48.
    OpenUrlCrossRefPubMed
  72. ↵
    1. Theodoropoulos VE,
    2. Lazaris ACh,
    3. Sofras F,
    4. Gerzelis I,
    5. Tsoukala V,
    6. Ghikonti I,
    7. Manikas K, and
    8. Kastriotis I
    (2004) Hypoxia-inducible factor 1 alpha expression correlates with angiogenesis and unfavorable prognosis in bladder cancer. Eur Urol 46:200–208.
    OpenUrlCrossRefPubMed
  73. ↵
    1. Vleugel MM,
    2. Greijer AE,
    3. Shvarts A,
    4. van der Groep P,
    5. van Berkel M,
    6. Aarbodem Y,
    7. van Tinteren H,
    8. Harris AL,
    9. van Diest PJ, and
    10. van der Wall E
    (2005) Differential prognostic impact of hypoxia induced and diffuse HIF-1alpha expression in invasive breast cancer. J Clin Pathol 58:172–177.
    OpenUrlAbstract/FREE Full Text
  74. ↵
    1. Winter SC,
    2. Shah KA,
    3. Han C,
    4. Campo L,
    5. Turley H,
    6. Leek R,
    7. Corbridge RJ,
    8. Cox GJ, and
    9. Harris AL
    (2006) The relation between hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha expression with anemia and outcome in surgically treated head and neck cancer. Cancer 107:757–766.
    OpenUrlCrossRefPubMed
  75. ↵
    1. Xia X,
    2. Lemieux ME,
    3. Li W,
    4. Carroll JS,
    5. Brown M,
    6. Liu XS, and
    7. Kung AL
    (2009a) Integrative analysis of HIF binding and transactivation reveals its role in maintaining histone methylation homeostasis. Proc Natl Acad Sci USA 106:4260–4265.
    OpenUrlAbstract/FREE Full Text
  76. ↵
    1. Xia X,
    2. Lemieux ME,
    3. Li W,
    4. Carroll JS,
    5. Brown M,
    6. Liu XS, and
    7. Kung AL
    (2009b) Integrative analysis of HIF binding and transactivation reveals its role in maintaining histone methylation homeostasis. Proc Natl Acad Sci USA 106:4260–4265.
    OpenUrlAbstract/FREE Full Text
  77. ↵
    1. Xia Y,
    2. Choi HK, and
    3. Lee K
    (2012) Recent advances in hypoxia-inducible factor (HIF)-1 inhibitors. Eur J Med Chem 49:24–40.
    OpenUrlCrossRefPubMed
  78. ↵
    1. Yamamoto Y,
    2. Ibusuki M,
    3. Okumura Y,
    4. Kawasoe T,
    5. Kai K,
    6. Iyama K, and
    7. Iwase H
    (2008) Hypoxia-inducible factor 1alpha is closely linked to an aggressive phenotype in breast cancer. Breast Cancer Res Treat 110:465–475.
    OpenUrlCrossRefPubMed
  79. ↵
    1. Yang J,
    2. Ledaki I,
    3. Turley H,
    4. Gatter KC,
    5. Montero JC,
    6. Li JL, and
    7. Harris AL
    (2009) Role of hypoxia-inducible factors in epigenetic regulation via histone demethylases. Ann N Y Acad Sci 1177:185–197.
    OpenUrlCrossRefPubMed
  80. ↵
    1. Zhang N,
    2. Fu Z,
    3. Linke S,
    4. Chicher J,
    5. Gorman JJ,
    6. Visk D,
    7. Haddad GG,
    8. Poellinger L,
    9. Peet DJ,
    10. Powell F,
    11. et al.
    (2010) The asparaginyl hydroxylase factor inhibiting HIF-1alpha is an essential regulator of metabolism. Cell Metab 11:364–378.
    OpenUrlCrossRefPubMed
  81. ↵
    1. Zheng SS,
    2. Chen XH,
    3. Yin X, and
    4. Zhang BH
    (2013) Prognostic significance of HIF-1α expression in hepatocellular carcinoma: a meta-analysis. PLoS One 8:e65753.
    OpenUrlCrossRefPubMed
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Molecular Responses to HIF-1α and Beyond

Jason Brocato, Yana Chervona and Max Costa
Molecular Pharmacology May 1, 2014, 85 (5) 651-657; DOI: https://doi.org/10.1124/mol.113.089623
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