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HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression
Open accessAbstract
Hypoxia-inducible factors (HIFs) are broadly expressed in human cancers, and HIF1α and HIF2α were previously suspected to promote tumour progression through largely overlapping functions. However, this relatively simple model has now been challenged in light of recent data from various approaches that reveal unique and sometimes opposing activities of these HIFα isoforms in both normal physiology and disease. These effects are mediated in part through the regulation of unique target genes, as well as through direct and indirect interactions with important oncoproteins and tumour suppressors, including MYC and p53. As HIF inhibitors are currently undergoing clinical evaluation as cancer therapeutics, a more thorough understanding of the unique roles performed by HIF1α and HIF2α in human neoplasia is warranted.
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“By recruiting transcriptional co-activators, HIFs regulate the expression of numerous genes involved in different processes including angiogenesis, metabolism, erythropoiesis, apoptosis, pH regulation, metastasis, and cellular differentiation (Semenza, 2003;Keith et al., 2012).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Keith et al., 2012
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“Deacetylation of HIF-2α by SIRT1, a deacetylase, increases HIF-2α's transcriptional activity, while deacetylation of HIF-1α results in transcriptional repression.”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Keith et al., 2012
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“Interestingly, the expression of VEGF, which is commonly considered a HIF-1α and HIF-2α target gene [19], was unchanged in all of the samples examined.”
From Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors (2014) · cites this paper as [19]
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“GLUT-1, known to be targeted by both HIF-1α and HIF-2α, was only decreased in 2 patients [19].”
From Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors (2014) · cites this paper as [19]
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1 retracted
RETRACTED: Acriflavine inhibits HIF-1 dimerization, tumor growth, and vascularization
Lee, K., Zhang, H., Qian, D. Z., Rey, S., Liu, J. O., & Semenza, G. L. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0909353106 · Cited by 451
RetractedTargeting HIF-1 for cancer therapy
Semenza, G. L. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1187 · Cited by 6,717
Wang, G. L., Jiang, B. H., Rue, E. A., & Semenza, G. L. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.12.5510 · Cited by 6,212
Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway.
Kaelin, W. G., & Ratcliffe, P. J. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.04.009 · Cited by 3,251
Blinded by the Light: The Growing Complexity of p53
Vousden, K. H., & Prives, C. (2009) · Cell · doi:10.1016/j.cell.2009.04.037 · Cited by 3,163
Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis
Carmeliet, P., Dor, Y., Herbert, J.-M., Fukumura, D., Brusselmans, K., Dewerchin, M., Neeman, M., Bono, F., Abramovitch, R., Maxwell, P., et al. (1998) · Nature · doi:10.1038/28867 · Cited by 2,502
Cellular and developmental control of O 2 homeostasis by hypoxia-inducible factor 1α
Iyer, N. V., Kotch, L. E., Agani, F., Leung, S. W., Laughner, E., Wenger, R. H., Gassmann, M., Gearhart, J. D., Lawler, A. M., Yu, A. Y., et al. (1998) · Genes & Development · doi:10.1101/gad.12.2.149 · Cited by 2,476
Hypoxia-inducible factors and the response to hypoxic stress
Majmundar, A. J., Wong, W. J., & Simon, M. C. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.09.022 · Cited by 2,380
Self-citationDefining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics
Semenza, G. L. (2010) · Oncogene · doi:10.1038/onc.2009.441 · Cited by 1,712
Hypoxia signalling in cancer and approaches to enforce tumour regression
Pouysségur, J., Dayan, F., & Mazure, N. M. (2006) · Nature · doi:10.1038/nature04871 · Cited by 1,676
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Items 901–1,000 of 1,008
Focus on Hypoxia-Related Pathways in Pediatric Osteosarcomas and Their Druggability
Pierrevelcin, M., Fuchs, Q., Lhermitte, B., Messé, M., Guérin, É., Weingertner, N., Martin, S., Lelong-Rebel, I. H., Nazon, C., Dontenwill, M., et al. (2020) · Cells · doi:10.3390/cells9091998 · Cited by 28
“To simplify, usually, mTORC1 upregulates HIF-1α via the S6 ribosom l protein (S6K), whereas mTORC2 directly activates HIF-2α [25,3 ,33].”
BackgroundInfluentialCrake, R., Burgess, E. R., Royds, J. A., Phillips, E., Vissers, M. C. M., & Dachs, G. U. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.619300 · Cited by 24
“Even though HIF-1 and HIF-2 have identical HREs, their response to hypoxia, tissue distribution, target genes and their pro- or anti-tumor effects are distinct (105).”
BackgroundSEMAPHORINS and their receptors: focus on the crosstalk between melanoma and hypoxia
Valentini, E., Martile, M. D., Bufalo, D. D., & D’Aguanno, S. (2021) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-021-01929-3 · Cited by 24
Todd, V. M., Vecchi, L. A., Clements, M. E., Snow, K. P., Ontko, C. D., Himmel, L. E., Pinelli, C. J., Rafat, M., & Johnson, R. W. (2021) · Communications Biology · doi:10.1038/s42003-021-02648-3 · Cited by 25
Self-citationLi, J., Lü, X., Wei, L., Ye, D., Lin, J., Tang, X., Cui, K., Yu, S., Xu, Y., & Liang, X. (2021) · Inflammation Research · doi:10.1007/s00011-021-01518-2 · Cited by 27
“Studies have demonstrated that PHDs play a key role in hypoxicischemic diseases, neovascularization, and tumor occurrence and development by downregulating HIF, and that PHD2 is the most important rate-limiting enzyme catalyzing the hydroxylation of HIF-1α under high-glucose and hypoxic conditions [21, 22].”
BackgroundMoving beyond the Tip of the Iceberg: DJ-1 Implications in Cancer Metabolism
Olivo, E., Chimia, M. L., Ceramella, J., Catalano, A. A., Chiaradonna, F., Sinicropi, M. S., Cuda, G., Iacopetta, D., & Scumaci, D. (2022) · Cells · doi:10.3390/cells11091432 · Cited by 25
“Regulation of the PI3K/Akt/mTOR pathway by DJ-1 is also responsible for stabilizing the subunits of another important transcription factor, HIF-1, under hypoxia, which is essential for tumor progression [57].”
BackgroundGao, Z., Wang, D., Yang, J., et al. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.114750 · Cited by 24
Decoding Allosteric Control in Hypoxia-Inducible Factors
Zhuang, J., Shang, Q., Rastinejad, F., & Wu, D. (2023) · Journal of Molecular Biology · doi:10.1016/j.jmb.2023.168352 · Cited by 25
Nsiah, N. Y., Morgan, A. B., Donkor, N., & Inman, D. M. (2023) · Scientific Reports · doi:10.1038/s41598-023-47942-8 · Cited by 27
Jiang, S., Zou, Z., Nie, P., Wen, R., Yingying, X., & Tang, J. (2015) · PLoS ONE · doi:10.1371/journal.pone.0132880 · Cited by 24
Morita, T., Nakano, D., Kitada, K., Morimoto, S., Ichihara, A., Hitomi, H., Kobori, H., Shiojima, I., & Nishiyama, A. (2015) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2015.03.053 · Cited by 24
“Anderson et al. (2013) have reported that the dysregulation of hypoxia-inducible factor (HIF)-2 alpha, which regulates p21 transcription (Keith et al., 2012), led to tissue iron overload during beta-thalassemia.”
BackgroundXu, W., Luo, F., Sun, B., Ye, H., Li, J., Shi, L., Liu, Y., Lü, X., Wang, B., Wang, Q., et al. (2015) · Toxicology Research · doi:10.1039/c5tx00225g · Cited by 24
Hypoxia-Inducible Factor-1α and Autoimmune Lupus, Arthritis
Yang, Z., & Liu, Y. (2016) · Inflammation · doi:10.1007/s10753-016-0337-z · Cited by 24
Tumour suppressor death-associated protein kinase targets cytoplasmic HIF-1α for Th17 suppression
Chou, T.-F., Chuang, Y.-T., Hsieh, W., Chang, P.-Y., Liu, H., Mo, S.-T., Hsu, T.-S., Miaw, S., Chen, R., Kimchi, A., et al. (2016) · Nature Communications · doi:10.1038/ncomms11904 · Cited by 25
Garrett-Bakelman, F. E., & Melnick, A. M. (2016) · Epigenomics · doi:10.2217/epi-2016-0008 · Cited by 25
Genome-independent hypoxic repression of estrogen receptor alpha in breast cancer cells
Padró, M., Louie, R. J., Lananna, B. V., Krieg, A. J., Timmerman, L., & Chan, D. A. (2017) · BMC Cancer · doi:10.1186/s12885-017-3140-9 · Cited by 25
Ligand-induced perturbation of the HIF-2α:ARNT dimer dynamics
Motta, S., Minici, C., Corrada, D., Bonati, L., & Pandini, A. (2018) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1006021 · Cited by 24
Drug resistance mechanisms of cancer stem-like cells and their therapeutic potential as drug targets
Murayama, T., & Gotoh, N. (2019) · Cancer Drug Resistance · doi:10.20517/cdr.2019.36 · Cited by 24
Macrophage HIF‐2α regulates tumor‐suppressive Spint1 in the tumor microenvironment
Susen, R. M., Bauer, R., Olesch, C., Fuhrmann, D. C., Fink, A. F., Dehne, N., Jain, A., Ebersberger, I., Schmid, T., & Brüne, B. (2019) · Molecular Carcinogenesis · doi:10.1002/mc.23103 · Cited by 24
Histone modifiers are oxygen sensors
Gallipoli, P., & Huntly, B. J. P. (2019) · Science · doi:10.1126/science.aaw8373 · Cited by 24
Targeting NKG2D in tumor surveillance
Hayakawa, Y. (2012) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2012.681378 · Cited by 24
Koizume, S., Takahashi, T., Yoshihara, M., Nakamura, Y., Ruf, W., Takenaka, K., Miyagi, E., & Miyagi, Y. (2019) · Thrombosis and Haemostasis · doi:10.1055/s-0039-1687876 · Cited by 23
Impact of Hypoxia over Human Viral Infections and Key Cellular Processes
Reyes, A., Duarte, L. F., Farías, M. A., Tognarelli, E. I., Kalergis, A. M., Bueno, S. M., & González, P. A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22157954 · Cited by 25
“High levels of MYC have been reported to sequester and bind to MAX, causing relief in the inhibition by HIF-1α [98].”
BackgroundInfluentialJonasch, E. W., Atkins, M. B., Chowdhury, S., & Mainwaring, P. N. (2022) · Cancers · doi:10.3390/cancers14030644 · Cited by 23
Jacquier, V., Gitenay, D., Fritsch, S., Bonnet, S., Győrffy, B., Jalaguier, S., Linares, L. K., Cavaillès, V., & Teyssier, C. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04277-3 · Cited by 23
“Although the regulation of HIF-α protein expression occurs at the protein level according to the oxygen level, augmented levels of HIF-α mRNA have been shown to increase HIF-α protein levels and activity [36].”
BackgroundInducing vascular normalization: A promising strategy for immunotherapy
Luo, X., Zou, W., Wei, Z., Yu, S., Zhao, Y., Wu, Y., Wang, A., & Lu, Y. (2022) · International Immunopharmacology · doi:10.1016/j.intimp.2022.109167 · Cited by 25
HIF-2α-induced upregulation of CD36 promotes the development of ccRCC
Liao, M., Li, Y., Xiao, A., Lu, Q., Zeng, H., Qin, H., Zheng, E., Luo, X., Chen, L., Ruan, X. Z., et al. (2022) · Experimental Cell Research · doi:10.1016/j.yexcr.2022.113389 · Cited by 26
Wang, J., Chen, X., Hu, H., Yao, M., Song, Y., Yang, A., Xu, X., Zhang, N., Gao, J., & Liu, B. (2021) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2021.02.034 · Cited by 23
Polymeric hydrogels as artificial extracellular microenvironments for cancer research
Park, K. M., & Gerecht, S. (2015) · European Polymer Journal · doi:10.1016/j.eurpolymj.2015.06.030 · Cited by 23
Rewiring cancer metabolism: oncogenic signaling pathways and targeted therapeutics
Lyu, S., Gildor, N., Zhang, Q. H., & Liao, C. (2025) · Science China Life Sciences · doi:10.1007/s11427-025-2979-3 · Cited by 27
“…s . structurally similar, have distinct roles in cancer: HIF-1 α is more involved in acute hypoxic responses and glycolysis, whereas HIF-2 α predominantly regulates angiogenesis, erythropoiesis, and stem cell maintenance, making it a key driver of ccRCC (Keith et al., 2012; Patel and Simon, 2008).”
Molecular targets on the horizon for kidney and urothelial cancer
Joaquim Bellmunt, B., Teh, B. T., Tortora, G., & Rosenberg, J. E. (2013) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2013.155 · Cited by 24
Liu, J., Wang, H., Zhang, M., Li, Y., Wang, R., Chen, H., Wang, B., Gao, X., Song, S., Wang, Y., et al. (2022) · Cancer Science · doi:10.1111/cas.15602 · Cited by 21
Immunotherapy, targeted therapy, and their cross talks in hepatocellular carcinoma
Liu, J., Park, K., Shen, Z., Lee, H. M., Geetha, P., Pakyari, M., & Chai, L. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1285370 · Cited by 24
“Elevated c-Myc expression is additionally capable of overriding HIF1 a - mediated inhibition, where HIF1 a and c-Myc together increase cell proliferation (98, 100).”
BackgroundThe oxygen puzzle in FLASH radiotherapy: A comprehensive review and experimental outlook
Scarmelotto, A., Delprat, V., Michiels, C., Lucas, S., & Heuskin, A. (2024) · Clinical and Translational Radiation Oncology · doi:10.1016/j.ctro.2024.100860 · Cited by 28
DUBs, New Members in the Hypoxia Signaling clUb
Schober, A. S., & Berra, E. (2016) · Frontiers in Oncology · doi:10.3389/fonc.2016.00053 · Cited by 22
Cheng, S., Pourteymoor, S., Alarcon, C. M., & Mohan, S. (2017) · Scientific Reports · doi:10.1038/srep45408 · Cited by 22
Identification of ARNT-regulated BIRC3 as the target factor in cadmium renal toxicity
Lee, J., Tokumoto, M., Hwang, G., Lee, M., & Satoh, M. (2017) · Scientific Reports · doi:10.1038/s41598-017-17494-9 · Cited by 22
Modeling Microenvironmental Regulation of Glioblastoma Stem Cells: A Biomaterials Perspective
Heffernan, J. M., & Sirianni, R. W. (2018) · Frontiers in Materials · doi:10.3389/fmats.2018.00007 · Cited by 21
Almendros, I., Martínez‐García, M. Á., Campos‐Rodríguez, F., Riveiro‐Falkenbach, E., Rodríguez‐Peralto, J. L., Nagore, E., Martorell, A., Blasco, L., Roca, J. B., Vives, E. C., et al. (2018) · Frontiers in Neurology · doi:10.3389/fneur.2018.00272 · Cited by 23
Targeting angiogenesis in metastatic renal cell carcinoma
Canino, C., Perrone, L., Bosco, E., Saltalamacchia, G., Mosca, A., Rizzo, M., & Porta, C. (2019) · Expert Review of Anticancer Therapy · doi:10.1080/14737140.2019.1574574 · Cited by 22
“On the other hand, HIF-2α subunit exclusively regulates cyclin D1; this protein, involved in cell cycle progression, is also induced in early VHL-defective RCC, suggesting a determining role of the VHL–HIF-2α–cyclin D1 axis in early RCC development [16].”
BackgroundHIF-2alpha: Achilles' heel of pseudohypoxic subtype paraganglioma and other related conditions
Tella, S. H., Taïeb, D., & Pacák, K. (2017) · European Journal of Cancer · doi:10.1016/j.ejca.2017.08.023 · Cited by 24
Peng, K., Zhuo, M., Li, M., Chen, Q., Mo, P., & Yu, C. (2021) · Oncogene · doi:10.1038/s41388-021-01678-9 · Cited by 22
Chen, M., Xiao, Z., Huang, Z., Xue, K., Xia, H., Zhou, J., Liao, D.-Y., Liang, Z.-J., Xiao, X., Wei, Q.-Z., et al. (2023) · International Journal of Biological Sciences · doi:10.7150/ijbs.85893 · Cited by 22
Kadyrov, F. F., Koenig, A. L., Amrute, J., Dun, H., Li, W., Weinheimer, C. J., Nigro, J. M., Kovács, A., Bredemeyer, A. L., Yang, S. H., et al. (2024) · Nature Cardiovascular Research · doi:10.1038/s44161-024-00553-6 · Cited by 30
“Overall, these results show that cells downstream of the Arg1 + differentiation trajectory are necessary for recovery from ischemic injury and the resHif1aKO phenotype, and that the inflammatory gene signature of Arg1 + macrophages is secondary to this phenotype.”
Rb1/Rbl1/Vhl loss induces mouse subretinal angiomatous proliferation and hemangioblastoma
Wei, R., Ren, X., Kong, H., Lv, Z., Chen, Y., Tang, Y., Wang, Y., Xiao, L., Yu, T., Hacibekiroglu, S., et al. (2019) · JCI Insight · doi:10.1172/jci.insight.127889 · Cited by 22
Sun, Y., Li, Y., Shi, S., & Dong, C. (2021) · Molecules · doi:10.3390/molecules26092703 · Cited by 21
Foglia, B., Sutti, S., Cannito, S., Rosso, C., Maggiora, M., Autelli, R., Novo, E., Bocca, C., Villano, G., Ramavath, N. N., et al. (2021) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2021.10.002 · Cited by 22
Pereira, M., Matuszewska, K., Jamieson, C., & Petrik, J. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.772349 · Cited by 21
Heck‐Swain, K., Li, J., Ruan, W., Yuan, X., Wang, Y., Koeppen, M., & Eltzschig, H. K. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.970415 · Cited by 21
“HIF2A is an isoform of HIF1A and several studies have identified either complementary or opposing functions to HIF1A (35, 55-58).”
BackgroundCracking the code: Deciphering the role of the tumor microenvironment in osteosarcoma metastasis
Jin, J., Cong, J., Lei, S., Zhang, Q., Zhong, X., Su, Y., Lu, M., Ma, Y., Li, Z., Wang, L., et al. (2023) · International Immunopharmacology · doi:10.1016/j.intimp.2023.110422 · Cited by 21
Hao, H., Hou, Y., Li, A., Niu, L., Li, S., He, B., Zhang, X., Song, H., Cai, R., Zhou, Y., et al. (2023) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14300 · Cited by 20
“40 Following SCI, a local hypoxic environment can induce overexpression of HIF-1 α , which in turn triggers a cascade of downstream signals.”
BackgroundEnvironmental and behavioral regulation of HIF-mitochondria crosstalk
Burtscher, J., Hohenauer, E., Burtscher, M., Millet, G. P., & Egg, M. (2023) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2023.06.015 · Cited by 27
Complex role of HIF in cancer: the known, the unknown, and the unexpected
Huang, E. L., Tiburcio, P. D. B., & Choi, H. (2014) · Hypoxia · doi:10.2147/hp.s50651 · Cited by 20
“21 HIF-1 α is sensitive to O 2 , owing to the presence of an O 2 -dependent degradation domain that mediates ubiquitin-proteasomal proteolysis.”
HIF proteins connect the RB-E2F factors to angiogenesis
Bakker, W. J., Weijts, B. G. M. W., Westendorp, B., & de Bruin, A. (2013) · Transcription · doi:10.4161/trns.23680 · Cited by 22
HIF‐1α protein is upregulated in HIF‐2α depleted cells via enhanced translation
Schulz, K. L., Milke, L., Rübsamen, D., Menrad, H., Schmid, T., & Brüne, B. (2012) · FEBS Letters · doi:10.1016/j.febslet.2012.04.039 · Cited by 21
HIFs Enhance the Transcriptional Activation and Splicing of Adrenomedullin
Sena, J. A., Wang, L., Pawlus, M. R., & Hu, C. (2014) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-13-0607 · Cited by 21
New Inhibitors of Angiogenesis with Antitumor Activity in Vivo
Marín‐Ramos, N. I., Alonso, D., Ortega‐Gutiérrez, S., et al. (2015) · Journal of Medicinal Chemistry · doi:10.1021/jm5019252 · Cited by 21
Emerging role of dopamine in neovascularization of pheochromocytoma and paraganglioma
Osinga, T. E., Links, T. P., Dullaart, R. P. F., Pacák, K., van der Horst‐Schrivers, A. N. A., Kerstens, M. N., & Kema, I. P. (2017) · The FASEB Journal · doi:10.1096/fj.201601131r · Cited by 28
Saint-Martin, A., Martínez-Ríos, J., Castañeda‐Patlán, M. C., Sarabia-Sánchez, M. Á., Tejeda‐Muñoz, N., Chinney-Herrera, A., Soldevila, G., Benelli, R., Santoyo‐Ramos, P., Poggi, A. D., et al. (2019) · Cancers · doi:10.3390/cancers11060755 · Cited by 21
Pan, S., Chiang, W., & Chen, Y. (2020) · Journal of the Formosan Medical Association · doi:10.1016/j.jfma.2020.06.006 · Cited by 24
Peroxisome-Deficiency and HIF-2α Signaling Are Negative Regulators of Ketohexokinase Expression
Eberhart, T., Schönenberger, M. J., Walter, K., Charles, K. N., Faust, P. L., & Kovacs, W. J. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00566 · Cited by 21
Tsai, Y., Wu, K., Chang, Y.-Y., Chang, W., Huang, Y., Jian, S., Tsai, P.-H., Lin, Y.-S., Chong, I., Hung, J., et al. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21145081 · Cited by 22
“Enhancement of HIF-2α has been linked to cancers in brain, head/neck, melanoma, lung and confers poor prognosis [10].”
BackgroundSALIDO, E. C., Timson, D. J., Betancor-Fernández, I., Palomino‐Morales, R., Anoz‐Carbonell, E., Pacheco‐García, J. L., Medina, M., & Pey, A. L. (2022) · Journal of Personalized Medicine · doi:10.3390/jpm12050747 · Cited by 22
Yokobori, T., Bao, P., Fukuchi, M., et al. (2015) · Annals of Surgical Oncology · doi:10.1245/s10434-015-4831-6 · Cited by 21
Zhou, S., Liu, R. R., Yuan, K., Yi, T., Zhao, X., Huang, C., & Wei, Y. (2012) · Mass Spectrometry Reviews · doi:10.1002/mas.21362 · Cited by 21
Chronic hypoxia impairs skeletal muscle repair via HIF‐2α stabilization
Yin, A., Fu, W., Elengickal, A. J., Kim, J., Liu, Y., Bigot, A., Mamchaoui, K., Call, J. A., & Yin, H. (2024) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.13436 · Cited by 22
Dual faces of angiogenesis: Mechanisms and therapeutic applications
Izadpanah, R., Izadpanah, A., & Alt, E. (2025) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2025.189494 · Cited by 22
Effects of hypoxia-inducible factor-1α silencing on the proliferation of CBRH-7919 hepatoma cells
Xu, L. (2013) · World Journal of Gastroenterology · doi:10.3748/wjg.v19.i11.1749 · Cited by 20
Identification of HOXA1 as a Novel Biomarker in Prognosis of Head and Neck Squamous Cell Carcinoma
Li, H., Wang, X., Zhang, M., Wang, M., Zhang, J., & Ma, S. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2020.602068 · Cited by 20
“Tumors adapt to hypoxic stress and create an immunosuppressive microenvironment suitable for survival (Keith et al., 2011).”
BackgroundMu, H., Ge, Y. P., Li, H., Wang, M., Cui, Y., Zhang, T., Song, T., & Liu, C. (2021) · Cellular Oncology · doi:10.1007/s13402-021-00625-w · Cited by 23
Townley, I. K., Babin, C. H., Murphy, T. E., Summa, C. M., & Rees, B. B. (2022) · Scientific Reports · doi:10.1038/s41598-022-26876-7 · Cited by 20
Xu, C., Huang, Z., Zhou, J., Jiang, W., Geng, J., Zhang, L., Pu, C., Li, L., Yu, C., & Huang, W. (2024) · Biosensors and Bioelectronics · doi:10.1016/j.bios.2024.116768 · Cited by 21
Wenger, R. H., Fuady, J. H., Bordoli, M. R., Abreu‐Rodríguez, I., Kristiansen, G., Hoogewijs, D., & Stiehl, D. P. (2014) · Hypoxia · doi:10.2147/hp.s54404 · Cited by 19
RSUME inhibits VHL and regulates its tumor suppressor function
Gerez, J., Tedesco, L., Bonfiglio, J. J., Fuertes, M., Barontini, M., Silberstein, S., Wu, Y., Renner, U., Páez-Pereda, M., Holsboer, F., et al. (2014) · Oncogene · doi:10.1038/onc.2014.407 · Cited by 20
Chai, D., Bao, Z., Hu, J., et al. (2013) · Journal of Huazhong University of Science and Technology [Medical Sciences] · doi:10.1007/s11596-013-1129-4 · Cited by 20
Evofosfamide, a new horizon in the treatment of pancreatic cancer
Pourmorteza, M., Rahman, Z. U., & Young, M. (2016) · Anti-Cancer Drugs · doi:10.1097/cad.0000000000000386 · Cited by 22
Chen, Y., Meng, F., Li, H., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.12520 · Cited by 20
The therapeutic potential of HIF-2 antagonism in renal cell carcinoma
Cuvillier, O. (2017) · Translational Andrology and Urology · doi:10.21037/tau.2017.01.12 · Cited by 21
“Despite their substantial sequence similarity and co-expression in various cancer cell types, HIF-1α and HIF-2α play non-overlapping roles in tumor progression (5).”
BackgroundHistone demethylase PHF8 regulates hypoxia signaling through HIF1α and H3K4me3
Maina, P. K., Shao, P., Jia, X., Liu, Q., Umesalma, S., Marin, M. J., Long, D., Concepción-Román, S., & Qi, H. H. (2017) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2017.07.005 · Cited by 19
Hsu, H.-L., Liao, P.-L., Cheng, Y., Huang, S.-H., Wu, C., Li, C.-H., & Kang, J. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20010157 · Cited by 20
Chen, D., Gu, K., & Wang, H. (2019) · Cancer Management and Research · doi:10.2147/cmar.s196170 · Cited by 21
“Both HIF-1α and HIF-2α can trigger the activation of EGFR and downstream targets.(47,48) Interestingly, HIFs are also EGFR downstream”
BackgroundCan We Predict Differentiated Thyroid Cancer Behavior? Role of Genetic and Molecular Markers
Ničiporuka, R., Nazarovs, J., Ozoliņš, A., et al. (2021) · Medicina · doi:10.3390/medicina57101131 · Cited by 20
HIF‐2α attenuates lymphangiogenesis by up‐regulating IGFBP1 in hepatocellular carcinoma
Geis, T., Popp, R., Hu, J., Fleming, I., Henke, N., Dehne, N., & Brüne, B. (2015) · Biology of the Cell · doi:10.1111/boc.201400079 · Cited by 19
“…studies have shown that HIF-1α and HIF-2α are structurally alike and regulate overlapping, but not identical sets of target genes, they promote highly divergent outcomes in cancer progression and may even have counteracting roles (Raval et al., 2005; Skuli and Simon, 2009; Keith et al., 2012).”
BackgroundHuman TM9SF4 Is a New Gene Down-Regulated by Hypoxia and Involved in Cell Adhesion of Leukemic Cells
Paolillo, R., Spinello, I., Quaranta, M. T., Pasquini, L., Pelosi, E., Lo‐Coco, F., Testa, U., & Labbaye, C. (2015) · PLoS ONE · doi:10.1371/journal.pone.0126968 · Cited by 20
“A genomic region of 163 bp containing the HRE sequence ACGTG [31, 32] in the putative TM9SF4 promoter region [NM_014742] was amplified in the immunoprecipitates by PCR using specific primers flanking the HRE site in the Prom-TM9SF4 region (forward, from -153 of the start codon ATG: 5’-CAGACTGTCGAGCAGGAG-3’; and revers…”
BackgroundMethodInfluentialHuang, E. L. (2013) · Science · doi:10.1126/science.1236966 · Cited by 20
A Reporter System Evaluates Tumorigenesis, Metastasis, β-catenin/MMP Regulation, and Druggability
Sogawa, C. A., Eguchi, T., Okusha, Y., Ono, K., Ohyama, K., Iizuka, M., Kawasaki, R., Hamada, Y., Takigawa, M., Sogawa, N., et al. (2019) · Tissue Engineering Part A · doi:10.1089/ten.tea.2018.0348 · Cited by 19
Kim, M., Lee, T. H., Lee, J. S., Lim, D., & Lee, P. C.-W. (2020) · Pharmaceuticals · doi:10.3390/ph13090208 · Cited by 19
Chang, L.-L., Lu, P., Yang, W., Hu, Y. W., Zheng, L., Zhao, Q., Lin, N., & Zhang, W. (2022) · Translational Oncology · doi:10.1016/j.tranon.2022.101421 · Cited by 20
“Higher levels of HIF-1α protein are observed in various kinds of human cancers compared to their normal tissues, correlating with relapse in cervical cancer, endometrial carcinoma, ovarian cancer and NSCLC [25,26].”
BackgroundUSP11 promotes glycolysis by regulating HIF ‐1α stability in hepatocellular carcinoma
Qiao, L., Hu, W., Li, L., Chen, X., Liu, L., & Wang, J. (2024) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.18017 · Cited by 19
Zhou, X. C., Xia, Q., Chen, M., Zhang, X., Huang, M., Zheng, X., Wang, S., Wu, B., & Du, Z. (2024) · Cell Biology International · doi:10.1002/cbin.12126 · Cited by 19
“Increasing evidence shows that HIF ‐ 1 α is critical in the development and metastasis of cancer (Chen et al., 2018; Keith et al., 2011; Lin et al., 2017).”
BackgroundRoles of β-Cell Hypoxia in the Progression of Type 2 Diabetes
Yamagata, K., Tsuyama, T., & Sato, Y. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25084186 · Cited by 20
“There are three forms of HIF-α (HIF-1 α , HIF-2 α , and HIF-3 α ), but the majority of HIF transcriptional responses seem to be attributed to HIF-1 α and HIF-2 α [28].”
BackgroundWu, Y., Cao, Y., Chen, L., Lai, X., Zhang, S., & Wang, S. (2024) · Biological Procedures Online · doi:10.1186/s12575-024-00245-2 · Cited by 20
“The expression of HIF1α is subjected to both transcriptional and post-translational regulation [127].”
BackgroundGong, J., Wang, S., Liu, J., et al. (2024) · Chemical Engineering Journal · doi:10.1016/j.cej.2024.155083 · Cited by 19
Nuclear speckles regulate functional programs in cancer
Alexander, K. A., Yu, R., Skuli, N., Coffey, N. J., Nguyen, S. C., Faunce, C. L., Huang, H., Dardani, I. P., Good, A. L., Lim, J., et al. (2025) · Nature Cell Biology · doi:10.1038/s41556-024-01570-0 · Cited by 28
“…cancers within the TCGA PanCan dataset have more heterogeneous aetiologies, ccRCC is typified by loss of function of the VHL gene 24 . pVHL encoded by VHL is a negative regulator of hypoxia-inducible transcription factors HIF-1α and HIF-2α, of which HIF-2α is proposed to drive oncogenesis 24–26 .”
Self-citationMolecular mechanisms of effectiveness of novel therapies in multiple myeloma
Bianchi, G., & Ghobrial, I. M. (2012) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.3109/10428194.2012.706287 · Cited by 19
Anti-angiogenic potential of an ethanol extract of Annona atemoya seeds in vitro and in vivo
Yi, J.-M., Park, J.-S., Lee, J. H., Hong, J. T., Bang, O., & Kim, N. S. (2014) · BMC Complementary and Alternative Medicine · doi:10.1186/1472-6882-14-353 · Cited by 19
Karetsi, E., Ιωάννου, Μ., Kerenidi, T., Minas, M., Molyvdas, P. A., Gourgoulianis, K. I., & Paraskeva, E. (2012) · Clinics · doi:10.6061/clinics/2012(12)05 · Cited by 19
PITX1, a specificity determinant in the HIF-1α-mediated transcriptional response to hypoxia
Mudie, S., Bandarra, D., Batie, M., Biddlestone, J., Moniz, S., Ortmann, B. M., Shmakova, A., & Rocha, S. (2014) · Cell Cycle · doi:10.4161/15384101.2014.972889 · Cited by 20
Silveira, V. S., Freire, B. M. R., Borges, K. S., Andrade, A. F., Cruzeiro, G. A. V., Sabino, J. P. J., Glass, M. L., Yunes, J. A., Brandalise, S. R., Tone, L. G., et al. (2013) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.3109/10428194.2013.858812 · Cited by 19
Wang, Y., Liu, B., Li, F., Zhang, Y., Gao, X., Wang, Y., & Zhou, H. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1274239 · Cited by 18
Metadata
- Authors
- Keith, B., Johnson, R. S., & Simon, M. C.
- Affiliations
- Abramson Cancer Center (US)
- University of California San Diego (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Simon, M. Celeste
- Venue
- Nature Reviews Cancer
- Published
- 2011-12-15
- Volume
- 12
- Issue
- 1
- Pages
- 9-22
- ISSN
- 1474-175X (ISSN-L)
- 1474-1768
- PMC
- PMC3401912
- OpenAlex
- W1998664010
- Cited by
- 1,693
- References
- 197
- Citations by year
- 2026: 82 · 2025: 82 · 2024: 112 · 2023: 116 · 2022: 126 · 2021: 135 · 2020: 118 · 2019: 124 · 2018: 123 · 2017: 117 · 2016: 112 · 2015: 112 · 2014: 141 · 2013: 122 · 2012: 70
- FWCI
- 7.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature reviews. Cancer (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- Wellcome Trust (092738/Z/10/Z)
- National Heart, Lung, and Blood Institute (R01HL066310)
- National Cancer Institute (R01CA158301)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Kruppel-like factors research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- HIF-1α, HIF-2α, hypoxia-inducible factor, tumor hypoxia, tumor progression, HIF target genes, c-Myc, p53, HIF inhibitors, cancer therapeutics, oxygen sensing
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Endothelial PAS Domain-Containing Protein 1, Acetylation, Animals, Gene Expression Regulation, Humans, Neoplasms, Protein Processing, Post-Translational, Proteins, Cell Hypoxia, Genes, p53, Genes, myc, Disease Progression, Multiprotein Complexes, Cell Proliferation, Basic Helix-Loop-Helix Proteins, Hypoxia-Inducible Factor 1, alpha Subunit, TOR Serine-Threonine Kinases
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