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HIF-1 in cancer therapy: two decade long story of a transcription factor
Open accessAbstract
Background: Oxygen (O2) homeostasis is an indispensable requirement of eukaryotes. O2 concentration in cellular milieu is defined as normoxia (∼21% O2), physoxia (∼1–13% O2) or hypoxia (∼0.1–1% O2). Hypoxia, a striking micro-environmental feature in tumorigenesis, is countered by tumor cells via induction of O2 governed transcription factor, hypoxia inducible factor-1 (HIF-1). Post discovery, HIF-1 has emerged as a promising anticancer therapeutic target during the last two decades. Recent reports have highlighted that enhanced levels of HIF-1 correlate with tumor metastasis leading to poor patient prognosis.Material and methods: A systematic search in PubMed and SciFinder for the literature on HIF-1 biology and therapeutic importance in cancer was carried out.Results: This review highlights the initial description as well as the recent insights into HIF-1 biology and regulation. We have focused on emerging data regarding varied classes of HIF-1 target genes affecting various levels of crosstalk among tumorigenic pathways. We have emphasized on the fact that HIF-1 acts as a networking hub coordinating activities of multiple signaling molecules influencing tumorigenesis. Emerging evidences indicate role of many HIF-induced proteomic and genomic alterations in malignant progression by mediating a myriad of genes stimulating angiogenesis, anaerobic metabolism and survival of cancer cells in O2-deficient microenvironment.Conclusions: Better understanding of the crucial role of HIF-1 in carcinogenesis could offer promising new avenues to researchers and aid in elucidating various open issues regarding the use of HIF-1 as an anticancer therapeutic target. In spite of large efforts in this field, many questions still remain unanswered. Hence, future investigations are necessary to devise, assess and refine methods for translating previous research efforts into novel clinical practices in cancer treatment.
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“However, no specific HIF inhibitor has been approved for clinical use8.”
From Liposomal Formulation of HIF-1α Inhibitor Echinomycin Eliminates Established Metastases of Triple-negative Breast Cancer (2020) · cites this paper as [8]
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“HIF-1α drives tumor progression because it orchestrates fundamental processes such as angiogenesis, glycolytic switch, and metastasis8.”
From Liposomal Formulation of HIF-1α Inhibitor Echinomycin Eliminates Established Metastases of Triple-negative Breast Cancer (2020) · cites this paper as [8]
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“Since the discovery of HIFs, many inhibitors with diverse modes of action have been identified, but none have progressed to clinical use [119].”
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“Whereas under hypoxic conditions, impaired hydroxylation process stabilizes the HIF1a protein, furthermore HIF1a will translocate into nuclear and dimerize with HIF1b to transactivate the target genes which relate with glucose metabolism, angiogenesis, cell proliferation, invasion and metastasis (reviewed in Pawlus an…”
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“However, the role of HIFs in cancer development extends beyond angiogenesis, and includes reprograming metabolism, regulating cell proliferation and survival, and increasing therapeutic resistance[17].”
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“promoting tumor cell growth, vascularization, and metastasis [7].”
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“In contrast to the Snitrosation of HIF-1α at cysteine 800 that takes place under hypoxia and is required for HIF-1-mediated transcription (reviewed in [16]), the S-nitrosation of HIF-1α at cysteine 533 can occur in normoxic tumors undergoing radiation exposure [105].”
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Čerychová, R., & Pavlínková, G. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00460 · Cited by 141
“Systemic administration of small-molecule inhibitors of HIF-1 activity with anticancer effects that impairs both vascular and metabolic adaptations have been successfully used in a number of preclinical studies (138).”
BackgroundEnolase 1, a Moonlighting Protein, as a Potential Target for Cancer Treatment
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“In the cancer metabolic reprogramming, ENO1 stimulates cancer cells to create energy largely by disintegration of glucose in a non-oxidative manner rather than typical oxidative phosphorylation (17,18).”
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“Furthermore, other agents, such as wortmannin, temsirolimus and camptothecin, have been proved to inhibit HIF-1α protein translation by targeting corresponding genes [138].”
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“HIF-1α promotes tumor progression by regulating glycolysis, angiogenesis, and cell cycle progression of tumor cells [26, 27].”
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“proliferation/viability, which has a crucial role in tumor survival and progression, leading to the increased possibility of metastasis as well as mortality rates clinically[58].”
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“Further studies allowed for new glycolytic enzymes influenced by HIF-1α to be determined, namely, hexokinase 1, hexokinase 2 (Soni and Padwad, 2017), enolase 1, aldolase A, and phosphofructokinase L (Iyer et al.”
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“Under hypoxic conditions, HIF-1α accumulates in the cytosol and is translocated to the nucleus, thereby forming active HIF-1α with HIF-1β and regulating downstream target genes transcriptionally.(21) In this study, DKC1 can positively regulate HIF1α in hypoxic and normoxic environments (Fig.”
BackgroundNanomedicine Strategies in Conquering and Utilizing the Cancer Hypoxia Environment
Pan, Y., Liu, L., Mou, X., & Cai, Y. (2023) · ACS Nano · doi:10.1021/acsnano.3c07763 · Cited by 98
Cancer-Associated Fibroblasts in the Hypoxic Tumor Microenvironment
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Molecular Crosstalk Between MYC and HIF in Cancer
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“Most of the reported HIF1 inhibitors were originally used for targeting other endogenous proteins and later they were found to inhibit HIF1 activity (Masoud and Li, 2015; Wigerup et al., 2016; Soni and Padwad, 2017).”
BackgroundInfluentialBNIP3 promotes HIF‐1α‐driven melanoma growth by curbing intracellular iron homeostasis
Vara‐Pérez, M., Rossi, M., den Haute, C. V., Maes, H., Sassano, M. L., Venkataramani, V., Michalke, B., Romano, E., Rillaerts, K., Garg, A. D., et al. (2021) · The EMBO Journal · doi:10.15252/embj.2020106214 · Cited by 89
“…including: (i) Glut1, Hk2, Pdk1, Pkm2, and Ldha are well-established HIF-1 α targets and HIF-1 α is a master regulator of the Warburg effect in melanoma (Soni & Padwad, 2017; Lee et al, 2020); (ii) melanoma cells harbor constitutively high levels of HIF-1 α (Kuphal et al, 2010; Mart (cid:1) ı…”
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“G HNSCC Squamous cell carcinoma of the head and neck HRE Hypoxia responsive element Hsp90 Heat shock protein‑90 ICB Immune checkpoint blockade IL‑1β Interleukin‑1β MDR1 Multidrug resistant protein 1 MDSC Myeloid‑derived suppressor cells MHC Major histocompatibility complex MMP Matrix metalloproteinase MTD Maximum tole…”
BackgroundInfluentialHypoxia and HIF-1α Regulate Collagen Production in Keloids
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Role of hypoxia inducible factor-1 in cancer stem cells (Review)
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“HIF‐1β is stably expressed in cells and maintains the stability of HIF‐1 (21,22).”
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“HIF-1α Nuclei Angiogenesis, erythropoiesis, cellular proliferation, survival, vascular remodeling, tumorigenesis, invasion, metastasis [16]”
Ribeiro, R., Carvalho, M. J., Gonçalves, J., & Moreira, J. N. (2022) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2022.903065 · Cited by 86
“In spite of the search for molecular targets involved in hypoxia to overcome chemoresistance, no clinical benefit has been reported so far in this context (Soni and Padwad, 2017).”
BackgroundModulation of the tumor microenvironment (TME) by melatonin
Qi, M., & Najafi, M. (2021) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2021.174365 · Cited by 82
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“Virchow first proposed that some tumors may arise from embryo-like cells and that cancer cells have properties reminiscent of stem cells reported in 1855 (1).”
Hypoxia-Inducible Factors as an Alternative Source of Treatment Strategy for Cancer
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“HIF-1 stimulates genetic transcription such as proteases that degrade cathepsin C (CTSC), matrix metalloproteinase 2, 9, and 14, and the urokinase plasminogen activator receptor or remodel lysyl oxidase (LOX); the extracellular matrices within are of metastasis [5]”
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Xu, J.-Q., Fu, Y.-L., Zhang, J., Zhang, K.-Y., Ma, J., Tang, J.-Y., Zhang, Z.-W., & Zhou, Z.-Y. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1037341 · Cited by 75
“Most of the key glycolytic enzymes are affected by MYC and HIF-1α in tumor glycolysis metabolism (Stine et al., 2015; Soni and Padwad, 2017).”
BackgroundMutant p53 and Cellular Stress Pathways: A Criminal Alliance That Promotes Cancer Progression
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“HIF-1 is considered the main effector of the cellular response to hypoxia inducing the transcription of target genes involved in many aspects of cancer progression, including angiogenesis, metabolic adaptation, chemoresistance, apoptosis evasion, invasion and metastasis, therefore, its targeting is considered a useful…”
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“HIF-1 targets genes coding key elements of glucose metabolism such as glucose transporters, hexokinases, phosphofructokinase, or lactate dehydrogenase.(61) Because of the complexity of HIF-1 involvement in various pathways and mechanisms, targeting it as a potential anti-cancer therapy element suggests it is an option…”
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“A large body of evidence has shown increased expression of HIF-1α and HIF-2α inside tumour masses [141, 142].”
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“requires the presence of O2 and Fe+2 as co-factors and allows the binding of the VHL active complex to HIF α through its β domain, its ubiquitination and subsequent proteasome degradation [17,18].”
BackgroundPharmacological features, health benefits and clinical implications of honokiol
Khatoon, F., Ali, S., Kumar, V., Elasbali, A. M., Alhassan, H. H., Alharethi, S. H., Islam, A., & Hassan, M. I. (2023) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2022.2120541 · Cited by 50
“Hypoxia-induced neovascularisation led by HIF activation is the primary cause of the pathogenesis in all solid tumor and ischemic retinal diseases (Semenza, 2003; Soni & Padwad, 2017).”
González-Ruiz, R., Leyva‐Carrillo, L., Peregrino-Uriarte, A. B., & Yepiz-Plascencia, G. M. (2022) · Cell Stress and Chaperones · doi:10.1007/s12192-022-01265-1 · Cited by 46
Role of HIF-1α in the Responses of Tumors to Radiotherapy and Chemotherapy
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Transferrin receptor-involved HIF-1 signaling pathway in cervical cancer
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Hypoxia and its therapeutic possibilities in paediatric cancers
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Sweet Cherries as Anti-Cancer Agents: From Bioactive Compounds to Function
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“Moreover, in rat-induced esophageal tumors [102], anthocyanins from black raspberries decreased the levels of VEGF and hypoxia inducible factor-1, the main transcription factor governing the expression of genes and proteins implicated in the angiogenic process [103].”
BackgroundRedox regulation of cancer stem cells: Biology and therapeutic implications
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“Under normoxic conditions, HIF-1α is targeted for proteasomal degradation as a result of prolyl hydroxylation that is mediated by α-KGdependent prolyl hydroxylases [45, 46].”
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“HIF1A is a well-known factor involved in the adaptive metabolic response to hypoxia [28].”
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“The activity of HIFs as a master regulator of cellular metabolism has been well characterized in a variety of cancer models [30].”
BackgroundRole of Glucose Metabolism Reprogramming in the Pathogenesis of Cholangiocarcinoma
Pant, K., Richard, S., Peixoto, E., & Gradilone, S. A. (2020) · Frontiers in Medicine · doi:10.3389/fmed.2020.00113 · Cited by 45
“During hypoxia, prolyl hydroxylation of HIF is withdrawn, resulting in stability and transcriptional activity of the HIF-1 protein complex (35, 36).”
BackgroundBolland, H. R., Ma, T. S., Ramlee, S., Ramadan, K., & Hammond, E. M. (2021) · Biochemical Society Transactions · doi:10.1042/bst20200861 · Cited by 44
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Hypoxia-inducible factor 2α: a novel target in gliomas
Renfrow, J. J., Soike, M. H., Debinski, W., Ramkissoon, S. H., Mott, R. T., Frenkel, M. B., Sarkaria, J. N., Lesser, G. J., & Strowd, R. E. (2018) · Future Medicinal Chemistry · doi:10.4155/fmc-2018-0163 · Cited by 40
Hypoxia-induced cancer cell reprogramming: a review on how cancer stem cells arise
Abd, G. M., Laird, M. C., Ku, J. C., & Li, Y. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1227884 · Cited by 41
Targeting Stat3 signaling impairs the progression of bladder cancer in a mouse model.
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Functional Analysis of O-GlcNAcylation in Cancer Metastasis
Wu, D., Jin, J., Qiu, Z., Liu, D., & Luo, H. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.585288 · Cited by 40
Fischer, F., Grigolon, G., Benner, C., & Ristow, M. (2022) · Physiological Reviews · doi:10.1152/physrev.00017.2021 · Cited by 42
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Angiogenesis and Hepatocellular Carcinoma: From Molecular Mechanisms to Systemic Therapies
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“It triggers tumor cells invasion, acting in the epithelial–mesenchymal transition (EMT) process, increases cells proliferation and decreases apoptosis [42].”
BackgroundTargeting HIF-2α as therapy for advanced cancers
Murugesan, T., Rajajeyabalachandran, G., Kumar, S., Nagaraju, S., & Jegatheesan, S. K. (2018) · Drug Discovery Today · doi:10.1016/j.drudis.2018.05.003 · Cited by 41
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“HIF1α is ubiquitously expressed in both tumor and normal tissue limiting its therapeutic specificity [31, 32].”
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“For example, the M2 isoform of the pyruvate kinase, which is under the regulation of the hypoxia-inducible factor, enables redirecting glycolytic intermediates to other metabolic pathways and stimulates the increased transcriptional activity of the HIF factor by binding to the transactivation domain [42].”
BackgroundTherapeutic strategies for liver diseases based on redox control systems
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Oxidative stress as candidate therapeutic target to overcome microenvironmental protection of CLL
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Mitochondria: A Galaxy in the Hematopoietic and Leukemic Stem Cell Universe
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“Subsequently, HIF1a interacts with a constitutively expressed HIF1b subunit to form a complex able to coordinate the transcription of genes involved in the glycolytic process [98].”
BackgroundRamundo, V., Giribaldi, G., & Aldieri, E. (2021) · Cancers · doi:10.3390/cancers13123093 · Cited by 37
“Therefore, targeting specific mediators in these regulatory pathways may serve as novel therapeutic approaches for cancer treatment [51].”
BackgroundShaikat, A. H., Azad, S. M. A. K., Tamim, M. A. R., Ullah, M. S., Amin, M. N., Sabbir, M. K., Tarun, M. T. I., Mostaq, M. S., Sabrin, S., Mahmud, M. Z., et al. (2025) · Cancer Pathogenesis and Therapy · doi:10.1016/j.cpt.2025.07.003 · Cited by 37
“42 The interaction of these molecules with their particular receptors, such as the epidermal growth factor receptor ( EGFR ) and the insulin-like growth factor 1 receptor, starts signal transduction pathways that result in the synthesis of HIF-1 α and either supports cell survival or proliferation.”
Involvement of E3 Ligases and Deubiquitinases in the Control of HIF-α Subunit Abundance
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“HIF-1α is known to regulate the expression of more than 300 genes and noncoding RNAs [6,40], which control genomic stability, drug resistance, angiogenesis, vascular tone, glucose metabolism, cell proliferation, and survival.”
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Transcriptional regulation of FoxM1 by HIF‑1α mediates hypoxia‑induced EMT in prostate cancer
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“These genes are regulated by the activation of the transcription factor HIF-1α, which serves an important role for the HIF family (41,42).”
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Metabolic Modifications by Common Respiratory Viruses and Their Potential as New Antiviral Targets
Kleinehr, J., Wilden, J. J., Boergeling, Y., Ludwig, S., & Hrincius, E. R. (2021) · Viruses · doi:10.3390/v13102068 · Cited by 33
“[20] observed that via the stabilization of HIF-1, an important metabolic regulator [37], RSV shifts the cell metabolism primarily from very oxygen-demanding pathways towards glycolysis and the PPP.”
BackgroundHIPK2 role in the tumor–host interaction: Impact on fibroblasts transdifferentiation CAF‐like
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“HIPK2 corepresses hypoxia inducible factor 1α (HIF-1α),(10) a major player in cancer progression through transactivation of HIF-1 target genes involved in angiogenesis, glucose metabolism, chemotherapeutic resistance and invasion.(11) On the other hand, HIPK2 depletion activates β4 integrin transcription and the Akt p…”
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“Maintaining oxygen homeostasis is crucial for cell survival [6].”
BackgroundJalouli, M. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26041752 · Cited by 31
“The redundancy and overlap in the functions of these isoforms may impede the formulation of targeted therapeutic strategies for modulating autophagy in cancer cells [127].”
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“VEGF-A (a potent endothelial mitogen) is by far the most prominent protein among all these pro-angiogenic factors stimulated by HIF as it is highly expressed in several human tumors (216–218).”
Potential Roles of Hypoxia-Inducible Factor-1 in Alzheimer’s Disease: Beneficial or Detrimental?
Lin, T., Huang, C.-R., Lin, K.-J., Hsieh, Y.-H., Chen, S., Lin, Y., Chao, A., & Yang, D. (2024) · Antioxidants · doi:10.3390/antiox13111378 · Cited by 30
“…to accommodate the hypoxic conditions and serve as a network hub to coordinate relevant signaling molecules for the promotion of tumorigenesis [24,43] . in human cancers can modify cellular metabolisms; these include from oxidative phosphorylation to glycolysis, the enhanced synthesis of In…”
Molecular Functions of WWOX Potentially Involved in Cancer Development
Taouis, K., Driouch, K., Lidereau, R., & Lallemand, F. (2021) · Cells · doi:10.3390/cells10051051 · Cited by 28
“HIF1α, overexpressed in common human cancers, is essential to this cellular adaptation [96].”
Background
Metadata
- Authors
- Soni, S., & Padwad, Y. S.
- Affiliations
- Institute of Himalayan Bioresource Technology (IN)
- Corresponding author
- Padwad, Yogendra S.
- Venue
- Acta Oncologica
- Published
- 2017-03-30
- Volume
- 56
- Issue
- 4
- Pages
- 503-515
- ISSN
- 0284-186X (ISSN-L)
- 1651-226X
- OpenAlex
- W2599085091
- Cited by
- 251
- References
- 122
- Citations by year
- 2026: 6 · 2025: 16 · 2024: 16 · 2023: 35 · 2022: 34 · 2021: 38 · 2020: 41 · 2019: 43 · 2018: 20 · 2017: 1
- FWCI
- 2.92
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Locations
- Acta Oncologica (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Council of Scientific and Industrial Research
- Council for Scientific and Industrial Research (MLP0039)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Keywords
- HIF-1, tumor hypoxia, oxygen homeostasis, transcription factor regulation, HIF-1 target genes, tumor angiogenesis, anaerobic metabolism, metastasis, carcinogenesis, cancer therapy targets, tumor microenvironment
- MeSH terms
- Animals, Humans, Neoplasms, Cell Hypoxia, Hypoxia-Inducible Factor 1, alpha Subunit
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