Special Issue "Gene Regulation by HIFs during Hypoxia"

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (31 December 2018).

Special Issue Editor

Prof. Dr. George Simos
E-Mail Website
Guest Editor
Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, Panepistimiou 3, BIOPOLIS, Larissa 41500, Greece
Interests: Hypoxia; Cancer cell metabolism & signal transduction; Hypoxia-Inducible Factors (HIFs); Regulation of gene expression; Post-translational modification; Nuclear traffic; Apoptosis; Iron metabolism; Hepcidin
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Special Issue Information

Dear Colleagues,

Exposure of human cells and/or tissues to low oxygen conditions, which is termed hypoxia, characterizes healthy activities, such as intense muscular exercise and living at high altitudes, as well as many pathological conditions, including pulmonary diseases, ischemia, inflammatory disorders and cancer. Adaptation to hypoxic conditions requires dramatic changes in gene expression, orchestrated by the hypoxia inducible transcription factors HIF-1 and HIF-2.

Since the first break-through identification of HIF-1 in 1995 by Semenza and co-workers, we have learned a great deal, both about the mechanisms that regulate HIFs in response to oxygen concentration changes, and about HIF target genes, the products of which mediate metabolic reprogramming, angiogenesis, erythropoiesis and many other homeostatic changes that allow adaptation to hypoxia or lead to apoptosis and cell death under extreme lack of oxygen. These findings have established HIFs as major players in both health and disease and triggered a world-wide effort to find ways of controlling their activity for therapeutic purposes.

Investigations of single gene expression as well as genome-wide studies have shown that HIFs bind to a short consensus sequence termed Hypoxia Response Element (HRE). However, HREs are much more abundant in the human genome than the number of true HIF gene targets, making their prediction impossible and necessitating non-trivial experimental verification. In this respect, characterization of the genes directly regulated by hypoxia is an ongoing process, which continues to provide important information on the cellular pathways affected by hypoxia and their role in the hypoxic response. As drugs that target HIFs either as inhibitors, in the case of cancer, or as stimulants, in the case of defective erythropoiesis, have recently been developed and may soon enter the market, it becomes imperative to produce a full inventory of the genes, the expression of which is affected when HIF activity is modulated by medicinal agents.

Furthermore, the molecular/structural details and tissue or isoform specificity of the oxygen-dependent and oxygen-independent mechanisms that fine-tune HIF activity, control the choice of common or distinct HIF targets and affect the interaction of HIFs with chromatin and the transcriptional machinery are still a matter of intense investigation. Full delineation of these mechanisms and their spatio-temporal coordination can offer additional possibilities to artificially influence HIF-dependent gene expression as means for treating a disease.

Prof. George Simos
Guest Editor

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Keywords

  • hypoxia
  • HIF
  • chromatin
  • transcription
  • cancer
  • oxygen
  • metabolism
  • erythropoiesis

Published Papers (11 papers)

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Research

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Open AccessArticle
2-Oxonanonoidal Antibiotic Actinolactomycin Inhibits Cancer Progression by Suppressing HIF-1α
Cells 2019, 8(5), 439; https://doi.org/10.3390/cells8050439 - 10 May 2019
Abstract
HIF-1 serves as an important regulator in cell response to hypoxia. Due to its key role in promoting tumor survival and progression under hypoxia, HIF-1 has become a promising target of cancer therapy. Thus far, several HIF-1 inhibitors have been identified, most of [...] Read more.
HIF-1 serves as an important regulator in cell response to hypoxia. Due to its key role in promoting tumor survival and progression under hypoxia, HIF-1 has become a promising target of cancer therapy. Thus far, several HIF-1 inhibitors have been identified, most of which are from synthesized chemical compounds. Here, we report that ALM (ActinoLactoMycin), a compound extracted from metabolites of Streptomyces flavoretus, exhibits inhibitory effect on HIF-1α. Mechanistically, we found that ALM inhibited the translation of HIF-1α protein by suppressing mTOR signaling activity. Treatment with ALM induced cell apoptosis and growth inhibition of cancer cells both in vitro and in vivo in a HIF-1 dependent manner. More interestingly, low dose of ALM treatment enhanced the anti-tumor effect of Everolimus, an inhibitor of mTOR, suggesting its potential use in combination therapy of tumors, especially solid tumor patients. Thus, we identified a novel HIF-1α inhibitor from the metabolites of Streptomyces flavoretus, which shows promising anti-cancer potential. Full article
(This article belongs to the Special Issue Gene Regulation by HIFs during Hypoxia)
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Open AccessArticle
HIF-1α and HIF-2α Differently Regulate the Radiation Sensitivity of NSCLC Cells
Cells 2019, 8(1), 45; https://doi.org/10.3390/cells8010045 - 12 Jan 2019
Cited by 2
Abstract
The hypoxia-inducible transcription factors (HIF)-1/2α are the main oxygen sensors which regulate the adaptation to intratumoral hypoxia. The aim of this study was to assess the role of the HIF proteins in regulating the radiation response of a non-small cell lung cancer (NSCLC) [...] Read more.
The hypoxia-inducible transcription factors (HIF)-1/2α are the main oxygen sensors which regulate the adaptation to intratumoral hypoxia. The aim of this study was to assess the role of the HIF proteins in regulating the radiation response of a non-small cell lung cancer (NSCLC) in vitro model. To directly assess the unique and overlapping functions of HIF-1α and HIF-2α, we use CRISPR gene-editing to generate isogenic H1299 non-small cell lung carcinoma cells lacking HIF-1α, HIF-2α or both. We found that in HIF1 knockout cells, HIF-2α was strongly induced by hypoxia compared to wild type but the reverse was not seen in HIF2 knockout cells. Cells lacking HIF-1α were more radiation resistant than HIF2 knockout and wildtype cells upon hypoxia, which was associated with a reduced recruitment of γH2AX foci directly after irradiation and not due to differences in proliferation. Conversely, double-HIF1/2 knockout cells were most radiation sensitive and had increased γH2AX recruitment and cell cycle delay. Compensatory HIF-2α activity in HIF1 knockout cells is the main cause of this radioprotective effect. Under hypoxia, HIF1 knockout cells uniquely had a strong increase in lactate production and decrease in extracellular pH. Using genetically identical HIF-α isoform-deficient cells we identified a strong radiosensitizing of HIF1, but not of HIF2, which was associated with a reduced extracellular pH and reduced glycolysis. Full article
(This article belongs to the Special Issue Gene Regulation by HIFs during Hypoxia)
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Open AccessArticle
The Role of Tissue Oxygen Tension in Dengue Virus Replication
Cells 2018, 7(12), 241; https://doi.org/10.3390/cells7120241 - 01 Dec 2018
Cited by 1
Abstract
Low oxygen tension exerts a profound effect on the replication of several DNA and RNA viruses. In vitro propagation of Dengue virus (DENV) has been conventionally studied under atmospheric oxygen levels despite that in vivo, the tissue microenvironment is hypoxic. Here, we compared [...] Read more.
Low oxygen tension exerts a profound effect on the replication of several DNA and RNA viruses. In vitro propagation of Dengue virus (DENV) has been conventionally studied under atmospheric oxygen levels despite that in vivo, the tissue microenvironment is hypoxic. Here, we compared the efficiency of DENV replication in liver cells, monocytes, and epithelial cells under hypoxic and normoxic conditions, investigated the ability of DENV to induce a hypoxia response and metabolic reprogramming and determined the underlying molecular mechanism. In DENV-infected cells, hypoxia had no effect on virus entry and RNA translation, but enhanced RNA replication. Overexpression and silencing approaches as well as chemical inhibition and energy substrate exchanging experiments showed that hypoxia-mediated enhancement of DENV replication depends on the activation of the key metabolic regulators hypoxia-inducible factors 1α/2α (HIF-1α/2α) and the serine/threonine kinase AKT. Enhanced RNA replication correlates directly with an increase in anaerobic glycolysis producing elevated ATP levels. Additionally, DENV activates HIF and anaerobic glycolysis markers. Finally, reactive oxygen species were shown to contribute, at least in part through HIF, both to the hypoxia-mediated increase of DENV replication and to virus-induced hypoxic reprogramming. These suggest that DENV manipulates hypoxia response and oxygen-dependent metabolic reprogramming for efficient viral replication. Full article
(This article belongs to the Special Issue Gene Regulation by HIFs during Hypoxia)
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Open AccessArticle
TNFSF14/LIGHT, a Non-Canonical NF-κB Stimulus, Induces the HIF Pathway
Cells 2018, 7(8), 102; https://doi.org/10.3390/cells7080102 - 08 Aug 2018
Cited by 3
Abstract
Non-canonical NF-κB signalling plays important roles in the development and function of the immune system but it also is deregulated in a number of inflammatory diseases. Although, NF-κB and HIF crosstalk has been documented, this has only been described following canonical NF-κB stimulation, [...] Read more.
Non-canonical NF-κB signalling plays important roles in the development and function of the immune system but it also is deregulated in a number of inflammatory diseases. Although, NF-κB and HIF crosstalk has been documented, this has only been described following canonical NF-κB stimulation, involving RelA/p50 and the HIF-1 dimer. Here, we report that the non-canonical inducer TNFSF14/LIGHT leads to HIF induction and activation in cancer cells. We demonstrate that only HIF-2α is induced at the transcriptional level following non-canonical NF-κB activation, via a mechanism that is dependent on the p52 subunit. Furthermore, we demonstrate that p52 can bind to the HIF-2α promoter in cells. These results indicate that non-canonical NF-κB can lead to HIF signalling implicating HIF-2α as one of the downstream effectors of this pathway in cells. Full article
(This article belongs to the Special Issue Gene Regulation by HIFs during Hypoxia)
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Review

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Open AccessReview
Involvement of E3 Ligases and Deubiquitinases in the Control of HIF-α Subunit Abundance
Cells 2019, 8(6), 598; https://doi.org/10.3390/cells8060598 - 15 Jun 2019
Abstract
The ubiquitin and hypoxia-inducible factor (HIF) pathways are cellular processes involved in the regulation of a variety of cellular functions. Enzymes called ubiquitin E3 ligases perform protein ubiquitylation. The action of these enzymes can be counteracted by another group of enzymes called deubiquitinases [...] Read more.
The ubiquitin and hypoxia-inducible factor (HIF) pathways are cellular processes involved in the regulation of a variety of cellular functions. Enzymes called ubiquitin E3 ligases perform protein ubiquitylation. The action of these enzymes can be counteracted by another group of enzymes called deubiquitinases (DUBs), which remove ubiquitin from target proteins. The balanced action of these enzymes allows cells to adapt their protein content to a variety of cellular and environmental stress factors, including hypoxia. While hypoxia appears to be a powerful regulator of the ubiquitylation process, much less is known about the impact of DUBs on the HIF system and hypoxia-regulated DUBs. Moreover, hypoxia and DUBs play crucial roles in many diseases, such as cancer. Hence, DUBs are considered to be promising targets for cancer cell-specific treatment. Here, we review the current knowledge about the role DUBs play in the control of HIFs, the regulation of DUBs by hypoxia, and their implication in cancer progression. Full article
(This article belongs to the Special Issue Gene Regulation by HIFs during Hypoxia)
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Open AccessReview
Protein Hydroxylation by Hypoxia-Inducible Factor (HIF) Hydroxylases: Unique or Ubiquitous?
Cells 2019, 8(5), 384; https://doi.org/10.3390/cells8050384 - 26 Apr 2019
Cited by 5
Abstract
All metazoans that utilize molecular oxygen (O2) for metabolic purposes have the capacity to adapt to hypoxia, the condition that arises when O2 demand exceeds supply. This is mediated through activation of the hypoxia-inducible factor (HIF) pathway. At physiological oxygen [...] Read more.
All metazoans that utilize molecular oxygen (O2) for metabolic purposes have the capacity to adapt to hypoxia, the condition that arises when O2 demand exceeds supply. This is mediated through activation of the hypoxia-inducible factor (HIF) pathway. At physiological oxygen levels (normoxia), HIF-prolyl hydroxylases (PHDs) hydroxylate proline residues on HIF-α subunits leading to their destabilization by promoting ubiquitination by the von-Hippel Lindau (VHL) ubiquitin ligase and subsequent proteasomal degradation. HIF-α transactivation is also repressed in an O2-dependent way due to asparaginyl hydroxylation by the factor-inhibiting HIF (FIH). In hypoxia, the O2-dependent hydroxylation of HIF-α subunits by PHDs and FIH is reduced, resulting in HIF-α accumulation, dimerization with HIF-β and migration into the nucleus to induce an adaptive transcriptional response. Although HIFs are the canonical substrates for PHD- and FIH-mediated protein hydroxylation, increasing evidence indicates that these hydroxylases may also have alternative targets. In addition to PHD-conferred alterations in protein stability, there is now evidence that hydroxylation can affect protein activity and protein/protein interactions for alternative substrates. PHDs can be pharmacologically inhibited by a new class of drugs termed prolyl hydroxylase inhibitors which have recently been approved for the treatment of anemia associated with chronic kidney disease. The identification of alternative targets of HIF hydroxylases is important in order to fully elucidate the pharmacology of hydroxylase inhibitors (PHI). Despite significant technical advances, screening, detection and verification of alternative functional targets for PHDs and FIH remain challenging. In this review, we discuss recently proposed non-HIF targets for PHDs and FIH and provide an overview of the techniques used to identify these. Full article
(This article belongs to the Special Issue Gene Regulation by HIFs during Hypoxia)
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Open AccessReview
Regulation Is in the Air: The Relationship between Hypoxia and Epigenetics in Cancer
Cells 2019, 8(4), 300; https://doi.org/10.3390/cells8040300 - 01 Apr 2019
Cited by 4
Abstract
Hypoxia is an inherent condition of tumors and contributes to cancer development and progression. Hypoxia-inducible factors (HIFs) are the major transcription factors involved in response to low O2 levels, orchestrating the expression of hundreds of genes involved in cancer hallmarks’ acquisition and [...] Read more.
Hypoxia is an inherent condition of tumors and contributes to cancer development and progression. Hypoxia-inducible factors (HIFs) are the major transcription factors involved in response to low O2 levels, orchestrating the expression of hundreds of genes involved in cancer hallmarks’ acquisition and modulation of epigenetic mechanisms. Epigenetics refers to inheritable mechanisms responsible for regulating gene expression, including genes involved in the hypoxia response, without altering the sequence of DNA bases. The main epigenetic mechanisms are DNA methylation, non-coding RNAs, and histone modifications. These mechanisms are highly influenced by cell microenvironment, such as O2 levels. The balance and interaction between these pathways is essential for homeostasis and is directly linked to cellular metabolism. Some of the major players in the regulation of HIFs, such as prolyl hydroxylases, DNA methylation regulators, and histone modifiers require oxygen as a substrate, or have metabolic intermediates as cofactors, whose levels are altered during hypoxia. Furthermore, during pathological hypoxia, HIFs’ targets as well as alterations in epigenetic patterns impact several pathways linked to tumorigenesis, such as proliferation and apoptosis, among other hallmarks. Therefore, this review aims to elucidate the intricate relationship between hypoxia and epigenetic mechanisms, and its crucial impact on the acquisition of cancer hallmarks. Full article
(This article belongs to the Special Issue Gene Regulation by HIFs during Hypoxia)
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Open AccessReview
Hypoxia-Inducible Factors and the Regulation of Lipid Metabolism
Cells 2019, 8(3), 214; https://doi.org/10.3390/cells8030214 - 03 Mar 2019
Cited by 5
Abstract
Oxygen deprivation or hypoxia characterizes a number of serious pathological conditions and elicits a number of adaptive changes that are mainly mediated at the transcriptional level by the family of hypoxia-inducible factors (HIFs). The HIF target gene repertoire includes genes responsible for the [...] Read more.
Oxygen deprivation or hypoxia characterizes a number of serious pathological conditions and elicits a number of adaptive changes that are mainly mediated at the transcriptional level by the family of hypoxia-inducible factors (HIFs). The HIF target gene repertoire includes genes responsible for the regulation of metabolism, oxygen delivery and cell survival. Although the involvement of HIFs in the regulation of carbohydrate metabolism and the switch to anaerobic glycolysis under hypoxia is well established, their role in the control of lipid anabolism and catabolism remains still relatively obscure. Recent evidence indicates that many aspects of lipid metabolism are modified during hypoxia or in tumor cells in a HIF-dependent manner, contributing significantly to the pathogenesis and/or progression of cancer and metabolic disorders. However, direct transcriptional regulation by HIFs has been only demonstrated in relatively few cases, leaving open the exact and isoform-specific mechanisms that underlie HIF-dependency. This review summarizes the evidence for both direct and indirect roles of HIFs in the regulation of genes involved in lipid metabolism as well as the involvement of HIFs in various diseases as demonstrated by studies with transgenic animal models. Full article
(This article belongs to the Special Issue Gene Regulation by HIFs during Hypoxia)
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Open AccessReview
Hypoxia and Hypoxia-Inducible Factors in Kidney Injury and Repair
Cells 2019, 8(3), 207; https://doi.org/10.3390/cells8030207 - 28 Feb 2019
Cited by 9
Abstract
Acute kidney injury (AKI) is a major kidney disease characterized by an abrupt loss of renal function. Accumulating evidence indicates that incomplete or maladaptive repair after AKI can result in kidney fibrosis and the development and progression of chronic kidney disease (CKD). Hypoxia, [...] Read more.
Acute kidney injury (AKI) is a major kidney disease characterized by an abrupt loss of renal function. Accumulating evidence indicates that incomplete or maladaptive repair after AKI can result in kidney fibrosis and the development and progression of chronic kidney disease (CKD). Hypoxia, a condition of insufficient supply of oxygen to cells and tissues, occurs in both acute and chronic kidney diseases under a variety of clinical and experimental conditions. Hypoxia-inducible factors (HIFs) are the “master” transcription factors responsible for gene expression in hypoxia. Recent researches demonstrate that HIFs play an important role in kidney injury and repair by regulating HIF target genes, including microRNAs. However, there are controversies regarding the pathological roles of HIFs in kidney injury and repair. In this review, we describe the regulation, expression, and functions of HIFs, and their target genes and related functions. We also discuss the involvement of HIFs in AKI and kidney repair, presenting HIFs as effective therapeutic targets. Full article
(This article belongs to the Special Issue Gene Regulation by HIFs during Hypoxia)
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Open AccessReview
Hypoxia Pathway Proteins in Normal and Malignant Hematopoiesis
Cells 2019, 8(2), 155; https://doi.org/10.3390/cells8020155 - 13 Feb 2019
Cited by 2
Abstract
The regulation of oxygen (O2) levels is crucial in embryogenesis and adult life, as O2 controls a multitude of key cellular functions. Low oxygen levels (hypoxia) are relevant for tissue physiology as they are integral to adequate metabolism regulation and [...] Read more.
The regulation of oxygen (O2) levels is crucial in embryogenesis and adult life, as O2 controls a multitude of key cellular functions. Low oxygen levels (hypoxia) are relevant for tissue physiology as they are integral to adequate metabolism regulation and cell fate. Hence, the hypoxia response is of utmost importance for cell, organ and organism function and is dependent on the hypoxia-inducible factor (HIF) pathway. HIF pathway activity is strictly regulated by the family of oxygen-sensitive HIF prolyl hydroxylase domain (PHD) proteins. Physiologic hypoxia is a hallmark of the hematopoietic stem cell (HSC) niche in the bone marrow. This niche facilitates HSC quiescence and survival. The present review focuses on current knowledge and the many open questions regarding the impact of PHDs/HIFs and other proteins of the hypoxia pathway on the HSC niche and on normal and malignant hematopoiesis. Full article
(This article belongs to the Special Issue Gene Regulation by HIFs during Hypoxia)
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Open AccessFeature PaperReview
Translating the Hypoxic Response—The Role of HIF Protein Translation in the Cellular Response to Low Oxygen
Cells 2019, 8(2), 114; https://doi.org/10.3390/cells8020114 - 01 Feb 2019
Cited by 3
Abstract
Hypoxia-Inducible Factors (HIFs) play essential roles in the physiological response to low oxygen in all multicellular organisms, while their deregulation is associated with human diseases. HIF levels and activity are primarily controlled by the availability of the oxygen-sensitive HIFα subunits, which is mediated [...] Read more.
Hypoxia-Inducible Factors (HIFs) play essential roles in the physiological response to low oxygen in all multicellular organisms, while their deregulation is associated with human diseases. HIF levels and activity are primarily controlled by the availability of the oxygen-sensitive HIFα subunits, which is mediated by rapid alterations to the rates of HIFα protein production and degradation. While the pathways that control HIFα degradation are understood in great detail, much less is known about the targeted control of HIFα protein synthesis and what role this has in controlling HIF activity during the hypoxic response. This review will focus on the signalling pathways and RNA binding proteins that modulate HIFα mRNA half-life and/or translation rate, and their contribution to hypoxia-associated diseases. Full article
(This article belongs to the Special Issue Gene Regulation by HIFs during Hypoxia)
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