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1
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Abe K, Sasano T, Soejima Y, Fukayama H, Maeda S, Furukawa T. Hypermethylation of Hif3a and Ifltd1 is associated with atrial remodeling in pressure-overload murine model. Sci Rep 2025; 15:2699. [PMID: 39837857 PMCID: PMC11751168 DOI: 10.1038/s41598-025-85382-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Accepted: 01/02/2025] [Indexed: 01/23/2025] Open
Abstract
Atrial remodeling is a major pathophysiological mechanism of atrial fibrillation (AF). Atrial remodeling progresses with aging and background diseases, including hypertension, heart failure, and AF itself. However, its mechanism of action and reversibility have not been completely elucidated. In this study, we investigated the involvement of DNA methylation in atrial remodeling. Mice underwent transverse aortic constriction (TAC) to generate a pressure overload model. After 14 days, the TAC-operated mice showed a significant increase in the atrium/body weight ratio and deposition of collagen fibers in the atria. A comprehensive analysis using RNA-sequencing (RNA-Seq) and methyl-CpG-binding domain sequencing (MBD-Seq) in the left atrial tissue identified Hif3a and Ifltd1 as showing increased DNA methylation in their promoter regions and decreased RNA expression. In addition, we created a transient pressure overload model by removing the aortic constriction 3 or 7 days after the initial TAC procedure (R3 or R7 groups). A reduction in RNA expression was achieved at R3 for Hif3a and at R7 for Ifltd1. Heterozygous Dnmt1 gene-targeting mice (Dnmt1mut) showed disappearance of the reduction in RNA expression and an increase in the atrium/body weight ratio. Altogether, DNA methylation contributed to at least part of atrial remodeling in the pressure overload mouse model.
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Affiliation(s)
- Keiko Abe
- Department of Dental Anesthesiology and Orofacial Pain Management, Institute of Science Tokyo, Tokyo, Japan
- Department of Cardiovascular Medicine, Institute of Science Tokyo, 1-5-45, Yushima, Bunkyo-ku, Tokyo, Japan
| | - Tetsuo Sasano
- Department of Cardiovascular Medicine, Institute of Science Tokyo, 1-5-45, Yushima, Bunkyo-ku, Tokyo, Japan.
| | - Yurie Soejima
- Department of Pathology and Anatomical Sciences, Institute of Science Tokyo, Tokyo, Japan
| | - Haruhisa Fukayama
- Department of Dental Anesthesiology and Orofacial Pain Management, Institute of Science Tokyo, Tokyo, Japan
| | - Shigeru Maeda
- Department of Dental Anesthesiology and Orofacial Pain Management, Institute of Science Tokyo, Tokyo, Japan
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2
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Abu-Remaileh M, Persky NS, Lee Y, Root DE, Kaelin WG. Total loss of VHL gene function impairs neuroendocrine cancer cell fitness due to excessive HIF2α activity. Proc Natl Acad Sci U S A 2024; 121:e2410356121. [PMID: 39320914 PMCID: PMC11459182 DOI: 10.1073/pnas.2410356121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 08/27/2024] [Indexed: 09/26/2024] Open
Abstract
Loss-of-function germline von Hippel-Lindau (VHL) tumor suppressor mutations cause VHL disease, which predisposes individuals to kidney cancer, hemangioblastomas, and paragangliomas. The risk that a given VHL disease family will manifest some or all these tumor types is profoundly influenced by the VHL allele it carries. For example, almost all VHL disease families that develop paraganglioma have missense VHL mutations. VHL families with null VHL alleles develop kidney cancer and hemangioblastomas without a high risk of paraganglioma. The latter is surprising because the VHL gene product, pVHL, suppresses the HIF2 transcription factor and gain-of-function HIF2 mutations are also linked to paraganglioma. Paragangliomas arise from the sympathetic or parasympathetic nervous system. Given the lack of human paraganglioma cell lines, we studied the effects of inactivating VHL in neuroblastoma cell lines, which also arise from the sympathetic nervous system. We found that total loss of pVHL function profoundly impairs the fitness of neuroblastoma cell lines in a HIF2-dependent manner both ex vivo and in vivo. This fitness defect can be rescued by pVHL variants linked to paraganglioma, but not by pVHL variants associated with a low risk of paraganglioma. These findings suggest that HIF2 activity above a critical threshold prevents the development of paraganglioma.
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Affiliation(s)
- Muhannad Abu-Remaileh
- Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA02215
| | - Nicole S. Persky
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA02142
| | - Yenarae Lee
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA02142
| | - David E. Root
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA02142
| | - William G. Kaelin
- Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA02215
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA02142
- HHMI, Chevy Chase, MD20815
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Holomková K, Veselá B, Dadáková K, Sharpe PT, Lesot H, Matalová E, Švandová E. Hypoxia-inducible factors in postnatal mouse molar dental pulp development: insights into expression patterns, localisation and metabolic pathways. Pflugers Arch 2024; 476:1411-1421. [PMID: 39101996 DOI: 10.1007/s00424-024-03003-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 07/24/2024] [Accepted: 07/25/2024] [Indexed: 08/06/2024]
Abstract
Hypoxia is relevant to several physiological and pathological processes and this also applies for the tooth. The adaptive response to lowering oxygen concentration is mediated by hypoxia-inducible factors (HIFs). Since HIFs were shown to participate in the promotion of angiogenesis, stem cell survival, odontoblast differentiation and dentin formation, they may play a beneficial role in the tooth reparative processes. Although some data were generated in vitro, little is known about the in vivo context of HIFs in tooth development. In order to contribute to this field, the mouse mandibular first molar was used as a model.The expression and in situ localisation of HIFs were examined at postnatal (P) days P0, P7, P14, using RT-PCR and immunostaining. The expression pattern of a broad spectrum of hypoxia-related genes was monitored by customised PCR Arrays. Metabolic aspects were evaluated by determination of the lactate level and mRNA expression of the mitochondrial marker Nd1.The results show constant high mRNA expression of Hif1a, increasing expression of Hif2a, and very low expression of Hif3a during early postnatal molar development. In the examined period the localisation of HIFs in the nuclei of odontoblasts and the subodontoblastic layer identified their presence during odontoblastic differentiation. Additionally, the lower lactate level and higher expression of mitochondrial Nd1 in advanced development points to decreasing glycolysis during differentiation. Postnatal nuclear localisation of HIFs indicates a hypoxic state in specific areas of dental pulp as oxygen demands depend on physiological events such as crown and root dentin mineralization.
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Affiliation(s)
- Kateřina Holomková
- Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Brno, Czech Republic.
- Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
| | - Barbora Veselá
- Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Brno, Czech Republic
- Department of Physiology, Veterinary University, Brno, Czech Republic
| | - Kateřina Dadáková
- Department of Biochemistry, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Paul T Sharpe
- Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Brno, Czech Republic
- Centre for Craniofacial and Regenerative Biology, King's College London, London, UK
| | - Hervé Lesot
- Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Brno, Czech Republic
| | - Eva Matalová
- Department of Physiology, Veterinary University, Brno, Czech Republic
| | - Eva Švandová
- Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Brno, Czech Republic
- Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
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4
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Ohgaki R, Hirase Y, Xu M, Okanishi H, Kanai Y. LAT1 expression in colorectal cancer cells is unresponsive to HIF-1/2α accumulation under experimental hypoxia. Sci Rep 2024; 14:19635. [PMID: 39179631 PMCID: PMC11343765 DOI: 10.1038/s41598-024-70603-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 08/19/2024] [Indexed: 08/26/2024] Open
Abstract
L-type amino acid transporter 1 (LAT1) is upregulated in various cancer types and contributes to disease progression. Previous studies have demonstrated or suggested that hypoxia-inducible factors (HIFs), the key transcription factors in hypoxic responses, control the expression of LAT1 gene in several types of cancer cells. However, this regulatory relationship has not been investigated yet in colorectal cancer (CRC), one of the cancer types in which the increased LAT1 expression holds prognostic significance. In this study, we found that neither LAT1 mRNA nor protein is induced under hypoxic condition (1% O2) in CRC HT-29 cells in vitro, regardless of the prominent HIF-1/2α accumulation and HIFs-dependent upregulation of glucose transporter 1. The hypoxic treatment generally did not increase either the mRNA or protein expression of LAT1 in eight CRC cell lines tested, in contrast to the pronounced upregulation by amino acid restriction. Interestingly, knockdown of von Hippel-Lindau ubiquitin ligase to inhibit the proteasomal degradation of HIFs caused an accumulation of HIF-2α and increased the LAT1 expression in certain CRC cell lines. This study contributes to delineating the molecular mechanisms responsible for the pathological expression of LAT1 in CRC cells, emphasizing the ambiguity of HIFs-dependent transcriptional upregulation of LAT1 across cancer cells.
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Affiliation(s)
- Ryuichi Ohgaki
- Department of Bio-System Pharmacology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Osaka, 565-0871, Japan.
| | - Yuma Hirase
- Department of Bio-System Pharmacology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Minhui Xu
- Department of Bio-System Pharmacology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Hiroki Okanishi
- Department of Bio-System Pharmacology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yoshikatsu Kanai
- Department of Bio-System Pharmacology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Osaka, 565-0871, Japan.
- Department of Metabolic Reprogramming and Signal Regulation, Premium Research Institute for Human Metaverse Medicine (WPI-PRIMe), Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
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5
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Di Mattia M, Sallese M, Neri M, Lopetuso LR. Hypoxic Functional Regulation Pathways in the GI Tract: Focus on the HIF-1α and Microbiota's Crosstalk. Inflamm Bowel Dis 2024; 30:1406-1418. [PMID: 38484200 DOI: 10.1093/ibd/izae046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Indexed: 08/02/2024]
Abstract
Hypoxia is an essential gastrointestinal (GI) tract phenomenon that influences both physiologic and pathologic states. Hypoxia-inducible factors (HIFs), the primary drivers of cell adaptation to low-oxygen environments, have been identified as critical regulators of gut homeostasis: directly, through the induction of different proteins linked to intestinal barrier stabilization (ie, adherent proteins, tight junctions, mucins, integrins, intestinal trefoil factor, and adenosine); and indirectly, through the regulation of several immune cell types and the modulation of autophagy and inflammatory processes. Furthermore, hypoxia and HIF-related sensing pathways influence the delicate relationship existing between bacteria and mammalian host cells. In turn, gut commensals establish and maintain the physiologic hypoxia of the GI tract and HIF-α expression. Based on this premise, the goals of this review are to (1) highlight hypoxic molecular pathways in the GI tract, both in physiologic and pathophysiologic settings, such as inflammatory bowel disease; and (2) discuss a potential strategy for ameliorating gut-related disorders, by targeting HIF signaling, which can alleviate inflammatory processes, restore autophagy correct mechanisms, and benefit the host-microbiota equilibrium.
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Affiliation(s)
- Miriam Di Mattia
- Department of Medicine and Ageing Sciences, Gabriele d'Annunzio University of Chieti-Pescara, Chieti, Italy
- Center for Advanced Studies and Technology, Gabriele d'Annunzio University of Chieti-Pescara, Chieti, Italy
| | - Michele Sallese
- Department of Medicine and Ageing Sciences, Gabriele d'Annunzio University of Chieti-Pescara, Chieti, Italy
- Center for Advanced Studies and Technology, Gabriele d'Annunzio University of Chieti-Pescara, Chieti, Italy
| | - Matteo Neri
- Department of Medicine and Ageing Sciences, Gabriele d'Annunzio University of Chieti-Pescara, Chieti, Italy
- Center for Advanced Studies and Technology, Gabriele d'Annunzio University of Chieti-Pescara, Chieti, Italy
| | - Loris Riccardo Lopetuso
- Department of Medicine and Ageing Sciences, Gabriele d'Annunzio University of Chieti-Pescara, Chieti, Italy
- Center for Advanced Studies and Technology, Gabriele d'Annunzio University of Chieti-Pescara, Chieti, Italy
- Medicina Interna e Gastroenterologia, CEMAD Centro Malattie dell'Apparato Digerente, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
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6
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Kawahata T, Tanaka K, Oyama K, Ueda J, Okamoto K, Makino Y. HIF3A gene disruption causes abnormal alveoli structure and early neonatal death. PLoS One 2024; 19:e0300751. [PMID: 38717999 PMCID: PMC11078382 DOI: 10.1371/journal.pone.0300751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 03/04/2024] [Indexed: 05/12/2024] Open
Abstract
Transcriptional response to changes in oxygen concentration is mainly controlled by hypoxia-inducible transcription factors (HIFs). Besides regulation of hypoxia-responsible gene expression, HIF-3α has recently been shown to be involved in lung development and in the metabolic process of fat tissue. However, the precise mechanism for such properties of HIF-3α is still largely unknown. To this end, we generated HIF3A gene-disrupted mice by means of genome editing technology to explore the pleiotropic role of HIF-3α in development and physiology. We obtained adult mice carrying homozygous HIF3A gene mutations with comparable body weight and height to wild-type mice. However, the number of litters and ratio of homozygous mutation carriers born from the mating between homozygous mutant mice was lower than expected due to sporadic deaths on postnatal day 1. HIF3A gene-disrupted mice exhibited abnormal configuration of the lung such as a reduced number of alveoli and thickened alveolar walls. Transcriptome analysis showed, as well as genes associated with lung development, an upregulation of stearoyl-Coenzyme A desaturase 1, a pivotal enzyme for fatty acid metabolism. Analysis of fatty acid composition in the lung employing gas chromatography indicated an elevation in palmitoleic acid and a reduction in oleic acid, suggesting an imbalance in distribution of fatty acid, a constituent of lung surfactant. Accordingly, administration of glucocorticoid injections during pregnancy resulted in a restoration of normal alveolar counts and a decrease in neonatal mortality. In conclusion, these observations provide novel insights into a pivotal role of HIF-3α in the preservation of critically important structure and function of alveoli beyond the regulation of hypoxia-mediated gene expression.
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Affiliation(s)
- Tomoki Kawahata
- Division of Endocrinology, Metabolism, and Rheumatology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Kitaru Tanaka
- Division of Endocrinology, Metabolism, and Rheumatology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Kyohei Oyama
- Department of Cardiac Surgery, Asahikawa Medical University, Asahikawa, Japan
| | - Jun Ueda
- Department of Advanced Medical Science, Asahikawa Medical University, Asahikawa, Japan
| | - Kensaku Okamoto
- Division of Endocrinology, Metabolism, and Rheumatology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Yuichi Makino
- Center for Integrated Medical Education and Regional Symbiosis, Asahikawa Medical University, Asahikawa, Japan
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7
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Yuan X, Ruan W, Bobrow B, Carmeliet P, Eltzschig HK. Targeting hypoxia-inducible factors: therapeutic opportunities and challenges. Nat Rev Drug Discov 2024; 23:175-200. [PMID: 38123660 DOI: 10.1038/s41573-023-00848-6] [Citation(s) in RCA: 52] [Impact Index Per Article: 52.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/06/2023] [Indexed: 12/23/2023]
Abstract
Hypoxia-inducible factors (HIFs) are highly conserved transcription factors that are crucial for adaptation of metazoans to limited oxygen availability. Recently, HIF activation and inhibition have emerged as therapeutic targets in various human diseases. Pharmacologically desirable effects of HIF activation include erythropoiesis stimulation, cellular metabolism optimization during hypoxia and adaptive responses during ischaemia and inflammation. By contrast, HIF inhibition has been explored as a therapy for various cancers, retinal neovascularization and pulmonary hypertension. This Review discusses the biochemical mechanisms that control HIF stabilization and the molecular strategies that can be exploited pharmacologically to activate or inhibit HIFs. In addition, we examine medical conditions that benefit from targeting HIFs, the potential side effects of HIF activation or inhibition and future challenges in this field.
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Affiliation(s)
- Xiaoyi Yuan
- Department of Anaesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
| | - Wei Ruan
- Department of Anaesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
- Department of Anaesthesiology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Bentley Bobrow
- Department of Emergency Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Peter Carmeliet
- Laboratory of Angiogenesis & Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology, KU Leuven, Leuven, Belgium
- Laboratory of Angiogenesis & Vascular Heterogeneity, Department of Biomedicine, Aarhus University, Aarhus, Denmark
- Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Holger K Eltzschig
- Department of Anaesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
- Outcomes Research Consortium, Cleveland, OH, USA.
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Shi X, Gao F, Zhao X, Pei C, Zhu L, Zhang J, Li C, Li L, Kong X. Role of HIF in fish inflammation. FISH & SHELLFISH IMMUNOLOGY 2023; 143:109222. [PMID: 37956798 DOI: 10.1016/j.fsi.2023.109222] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 11/06/2023] [Accepted: 11/08/2023] [Indexed: 11/15/2023]
Abstract
The hypoxia-inducing factor (HIF) is a central transcription factor in cellular oxygen sensing and regulation. It is common that the inflammation always appears in many diseases, like infectious diseases in fishes, and the inflammation is often accompanied by hypoxia, as a hallmark of inflammation. Besides coordinating cellular responses to low oxygen, HIF-mediated hypoxia signaling pathway is also crucial for immune responses such as the regulations of innate immune cell phenotype and function, as well as metabolic reprogramming under the inflammation. However, the understanding of the molecular mechanisms by which HIFs regulate the inflammatory response in fish is still very limited. Here, we review the characteristics of HIF as well as its roles in innate immune cells and the infections caused by bacteria and viruses. The regulatory effects of HIF on the metabolic reprogramming of innate immune cells are also discussed and the future research directions are outlooked. This paper will serve as a reference for elucidating the molecular mechanism of HIF regulating inflammation and identifying treatment strategies to target HIF for fish disease.
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Affiliation(s)
- Xiaowei Shi
- Engineering Lab of Henan Province for Aquatic Animal Disease Control, College of Fisheries, Henan Normal University, Henan Province, PR China; Sanquan Medical College, Henan Province, PR China
| | - Feng Gao
- Engineering Lab of Henan Province for Aquatic Animal Disease Control, College of Fisheries, Henan Normal University, Henan Province, PR China
| | - Xianliang Zhao
- Engineering Lab of Henan Province for Aquatic Animal Disease Control, College of Fisheries, Henan Normal University, Henan Province, PR China
| | - Chao Pei
- Engineering Lab of Henan Province for Aquatic Animal Disease Control, College of Fisheries, Henan Normal University, Henan Province, PR China
| | - Lei Zhu
- Engineering Lab of Henan Province for Aquatic Animal Disease Control, College of Fisheries, Henan Normal University, Henan Province, PR China
| | - Jie Zhang
- Engineering Lab of Henan Province for Aquatic Animal Disease Control, College of Fisheries, Henan Normal University, Henan Province, PR China
| | - Chen Li
- Engineering Lab of Henan Province for Aquatic Animal Disease Control, College of Fisheries, Henan Normal University, Henan Province, PR China
| | - Li Li
- Engineering Lab of Henan Province for Aquatic Animal Disease Control, College of Fisheries, Henan Normal University, Henan Province, PR China
| | - Xianghui Kong
- Engineering Lab of Henan Province for Aquatic Animal Disease Control, College of Fisheries, Henan Normal University, Henan Province, PR China.
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González-Arzola K, Díaz-Quintana A. Mitochondrial Factors in the Cell Nucleus. Int J Mol Sci 2023; 24:13656. [PMID: 37686461 PMCID: PMC10563088 DOI: 10.3390/ijms241713656] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 08/31/2023] [Accepted: 08/31/2023] [Indexed: 09/10/2023] Open
Abstract
The origin of eukaryotic organisms involved the integration of mitochondria into the ancestor cell, with a massive gene transfer from the original proteobacterium to the host nucleus. Thus, mitochondrial performance relies on a mosaic of nuclear gene products from a variety of genomes. The concerted regulation of their synthesis is necessary for metabolic housekeeping and stress response. This governance involves crosstalk between mitochondrial, cytoplasmic, and nuclear factors. While anterograde and retrograde regulation preserve mitochondrial homeostasis, the mitochondria can modulate a wide set of nuclear genes in response to an extensive variety of conditions, whose response mechanisms often merge. In this review, we summarise how mitochondrial metabolites and proteins-encoded either in the nucleus or in the organelle-target the cell nucleus and exert different actions modulating gene expression and the chromatin state, or even causing DNA fragmentation in response to common stress conditions, such as hypoxia, oxidative stress, unfolded protein stress, and DNA damage.
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Affiliation(s)
- Katiuska González-Arzola
- Centro Andaluz de Biología Molecular y Medicina Regenerativa—CABIMER, Consejo Superior de Investigaciones Científicas—Universidad de Sevilla—Universidad Pablo de Olavide, 41092 Seville, Spain
- Departamento de Bioquímica Vegetal y Biología Molecular, Universidad de Sevilla, 41012 Seville, Spain
| | - Antonio Díaz-Quintana
- Departamento de Bioquímica Vegetal y Biología Molecular, Universidad de Sevilla, 41012 Seville, Spain
- Instituto de Investigaciones Químicas—cicCartuja, Universidad de Sevilla—C.S.I.C, 41092 Seville, Spain
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10
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Zheng X, Liang Y, Zhang C. Ferroptosis Regulated by Hypoxia in Cells. Cells 2023; 12:cells12071050. [PMID: 37048123 PMCID: PMC10093394 DOI: 10.3390/cells12071050] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/22/2023] [Accepted: 03/28/2023] [Indexed: 04/03/2023] Open
Abstract
Ferroptosis is an oxidative damage-related, iron-dependent regulated cell death with intracellular lipid peroxide accumulation, which is associated with many physiological and pathological processes. It exhibits unique features that are morphologically, biochemically, and immunologically distinct from other regulated cell death forms. Ferroptosis is regulated by iron metabolism, lipid metabolism, anti-oxidant defense systems, as well as various signal pathways. Hypoxia, which is found in a group of physiological and pathological conditions, can affect multiple cellular functions by activation of the hypoxia-inducible factor (HIF) signaling and other mechanisms. Emerging evidence demonstrated that hypoxia regulates ferroptosis in certain cell types and conditions. In this review, we summarize the basic mechanisms and regulations of ferroptosis and hypoxia, as well as the regulation of ferroptosis by hypoxia in physiological and pathological conditions, which may contribute to the numerous diseases therapies.
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Affiliation(s)
- Xiangnan Zheng
- College of Biological Science and Engineering, Fuzhou University, Fuzhou 350108, China
| | - Yuqiong Liang
- College of Biological Science and Engineering, Fuzhou University, Fuzhou 350108, China
| | - Cen Zhang
- College of Biological Science and Engineering, Fuzhou University, Fuzhou 350108, China
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Townley IK, Babin CH, Murphy TE, Summa CM, Rees BB. Genomic analysis of hypoxia inducible factor alpha in ray-finned fishes reveals missing Ohnologs and evidence of widespread positive selection. Sci Rep 2022; 12:22312. [PMID: 36566251 PMCID: PMC9789988 DOI: 10.1038/s41598-022-26876-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Accepted: 12/20/2022] [Indexed: 12/25/2022] Open
Abstract
As aquatic hypoxia worsens on a global scale, fishes will become increasingly challenged by low oxygen, and understanding the molecular basis of their response to hypoxia may help to better define the capacity of fishes to cope with this challenge. The hypoxia inducible factor (HIF) plays a critical role in the molecular response to hypoxia by activating the transcription of genes that serve to improve oxygen delivery to the tissues or enhance the capacity of tissues to function at low oxygen. The current study examines the molecular evolution of genes encoding the oxygen-dependent HIFα subunit (HIFA) in the ray-finned fishes (Actinopterygii). Genomic analyses demonstrate that several lineages retain four paralogs of HIFA predicted from two rounds of genome duplication at the base of vertebrate evolution, broaden the known distribution of teleost-specific HIFA paralogs, and provide evidence for salmonid-specific HIFA duplicates. Evolution of the HIFA gene family is characterized by widespread episodic positive selection at amino acid sites that potentially mediate protein stability, protein-protein interactions, and transcriptional regulation. HIFA transcript abundance depends upon paralog, tissue, and fish lineage. A phylogenetically-informed gene nomenclature is proposed along with avenues for future research on this critical family of transcription factors.
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Affiliation(s)
- Ian K. Townley
- Science Department, Saint George’s School, Spokane, WA 99208 USA
| | - Courtney H. Babin
- grid.266835.c0000 0001 2179 5031Department of Biological Sciences, University of New Orleans, New Orleans, LA 70148 USA
| | - Taylor E. Murphy
- grid.266835.c0000 0001 2179 5031Department of Biological Sciences, University of New Orleans, New Orleans, LA 70148 USA
| | - Christopher M. Summa
- grid.266835.c0000 0001 2179 5031Department of Computer Sciences, University of New Orleans, New Orleans, LA 70148 USA
| | - Bernard B. Rees
- grid.266835.c0000 0001 2179 5031Department of Biological Sciences, University of New Orleans, New Orleans, LA 70148 USA
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12
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Guo H, Huang J, Liang Y, Wang D, Zhang H. Focusing on the hypoxia-inducible factor pathway: role, regulation, and therapy for osteoarthritis. Eur J Med Res 2022; 27:288. [PMID: 36503684 PMCID: PMC9743529 DOI: 10.1186/s40001-022-00926-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Accepted: 12/02/2022] [Indexed: 12/14/2022] Open
Abstract
Osteoarthritis (OA) is a common chronic disabling disease that affects hundreds of millions of people around the world. The most important pathological feature is the rupture and loss of articular cartilage, and the characteristics of avascular joint tissues lead to limited repair ability. Currently, there is no effective treatment to prevent cartilage degeneration. Studies on the mechanism of cartilage metabolism revealed that hypoxia-inducible factors (HIFs) are key regulatory genes that maintain the balance of cartilage catabolism-matrix anabolism and are considered to be the major OA regulator and promising OA treatment target. Although the exact mechanism of HIFs in OA needs to be further clarified, many drugs that directly or indirectly act on HIF signaling pathways have been confirmed by animal experiments and regarded as promising treatments for OA. Targeting HIFs will provide a promising strategy for the development of new OA drugs. This article reviews the regulation of HIFs on intra-articular cartilage homeostasis and its influence on the progression of osteoarthritis and summarizes the recent advances in OA therapies targeting the HIF system.
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Affiliation(s)
- Hanhan Guo
- grid.263817.90000 0004 1773 1790Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, 518055 China
| | - Jianghong Huang
- grid.452847.80000 0004 6068 028XDepartment of Spine Surgery and Orthopedics, Shenzhen Second People’s Hospital (First Affiliated Hospital of Shenzhen University, Health Science Center), Shenzhen, 518035 China ,grid.12527.330000 0001 0662 3178Innovation Leading Engineering Doctor, Tsinghua University Shenzhen International Graduate School, Class 9 of 2020, Shenzhen, 518055 China
| | - Yujie Liang
- grid.452897.50000 0004 6091 8446Department of Child and Adolescent Psychiatry, Shenzhen Kangning Hospital, Shenzhen Mental Health Center, Shenzhen, 518020 China
| | - Daping Wang
- grid.263817.90000 0004 1773 1790Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, 518055 China ,grid.452847.80000 0004 6068 028XDepartment of Orthopedics, Shenzhen Intelligent Orthopaedics and Biomedical Innovation Platform, Guangdong Provincial Research Center for Artificial Intelligence and Digital Orthopedic Technology, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, 518000 China
| | - Huawei Zhang
- grid.263817.90000 0004 1773 1790Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, 518055 China ,grid.263817.90000 0004 1773 1790Guangdong Provincial Key Laboratory of Advanced Biomaterials, Southern University of Science and Technology, Shenzhen, 518055 China
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13
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Zethoven M, Martelotto L, Pattison A, Bowen B, Balachander S, Flynn A, Rossello FJ, Hogg A, Miller JA, Frysak Z, Grimmond S, Fishbein L, Tischler AS, Gill AJ, Hicks RJ, Dahia PLM, Clifton-Bligh R, Pacak K, Tothill RW. Single-nuclei and bulk-tissue gene-expression analysis of pheochromocytoma and paraganglioma links disease subtypes with tumor microenvironment. Nat Commun 2022; 13:6262. [PMID: 36271074 PMCID: PMC9587261 DOI: 10.1038/s41467-022-34011-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Accepted: 10/10/2022] [Indexed: 01/13/2023] Open
Abstract
Pheochromocytomas (PC) and paragangliomas (PG) are rare neuroendocrine tumors associated with autonomic nerves. Here we use single-nuclei RNA-seq and bulk-tissue gene-expression data to characterize the cellular composition of PCPG and normal adrenal tissues, refine tumor gene-expression subtypes and make clinical and genotypic associations. We confirm seven PCPG gene-expression subtypes with significant genotype and clinical associations. Tumors with mutations in VHL, SDH-encoding genes (SDHx) or MAML3-fusions are characterized by hypoxia-inducible factor signaling and neoangiogenesis. PCPG have few infiltrating lymphocytes but abundant macrophages. While neoplastic cells transcriptionally resemble mature chromaffin cells, early chromaffin and neuroblast markers are also features of some PCPG subtypes. The gene-expression profile of metastatic SDHx-related PCPG indicates these tumors have elevated cellular proliferation and a lower number of non-neoplastic Schwann-cell-like cells, while GPR139 is a potential theranostic target. Our findings therefore clarify the diverse transcriptional programs and cellular composition of PCPG and identify biomarkers of potential clinical significance.
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Affiliation(s)
| | - Luciano Martelotto
- Centre for Cancer Research and Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia
| | - Andrew Pattison
- Centre for Cancer Research and Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia
| | - Blake Bowen
- Centre for Cancer Research and Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia
| | - Shiva Balachander
- Centre for Cancer Research and Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia
| | - Aidan Flynn
- Centre for Cancer Research and Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia
| | - Fernando J Rossello
- Centre for Cancer Research and Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia
| | - Annette Hogg
- Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Julie A Miller
- Department of Surgery, Royal Melbourne Hospital, Parkville, VIC, Australia.,Department of Surgery, Epworth Hospital, Richmond, VIC, Australia
| | - Zdenek Frysak
- 3rd Department of Internal Medicine - Nephrology, Rheumatology and Endocrinology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Olomouc, Czech Republic
| | - Sean Grimmond
- Centre for Cancer Research and Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia
| | - Lauren Fishbein
- Department of Medicine, Division of Endocrinology, Metabolism, Diabetes, University of Colorado, Aurora, CO, USA
| | | | - Anthony J Gill
- Sydney Medical School, University of Sydney, Sydney, NSW, Australia.,Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, NSW, Australia.,NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, NSW, Australia
| | - Rodney J Hicks
- Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Patricia L M Dahia
- Div. Hematology and Medical Oncology, Department of Medicine, Mays Cancer Center, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, TX, USA
| | - Roderick Clifton-Bligh
- Sydney Medical School, University of Sydney, Sydney, NSW, Australia.,Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, NSW, Australia
| | - Karel Pacak
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA
| | - Richard W Tothill
- Centre for Cancer Research and Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia. .,Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.
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14
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Ross BX, Jia L, Kong D, Wang T, Yao J, Hager HM, Abcouwer SF, Zacks DN. Hypoxia-Inducible Factor-1α in Rods Is Neuroprotective Following Retinal Detachment. Invest Ophthalmol Vis Sci 2022; 63:7. [PMID: 36223101 PMCID: PMC9583748 DOI: 10.1167/iovs.63.11.7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 09/22/2022] [Indexed: 02/02/2023] Open
Abstract
Purpose Following retinal detachment (RD) photoreceptors (PRs) sustain hypoxic stress and eventually die. Hypoxia-inducible factor-1α (HIF-1α) plays a central role in cellular adaptation to hypoxia. The purpose of this study is to determine the necessity of HIF-1α on PR cell survival after RD. Methods Experimental RD was created in mice by injection of hyaluronic acid (1%) into the subretinal space. Mice with conditional HIF-1α knockout in rods (denoted as HIF-1αΔrod) were used. HIF-1α expression in retinas was measured real-time polymerase chain reaction (RT-PCR) and Western blotting. PR cell death after RD was evaluated using TUNEL assay. Optical coherence tomography (OCT) and histology were used to evaluate retinal layer thicknesses and PR cell densities. A hypoxia signaling pathway PCR array was used to examine the expression of HIF-1α target genes after RD. Results HIF-1α protein levels were significantly increased after RD, and depletion of HIF-1α in rods blunted this increase. A compensatory increase of HIF-2α protein was observed in HIF-1αΔrod mice. Conditional knockout (cKO) of HIF-1α in rods did not lead to any morphologic change in attached retinas but resulted in significantly increased PR cell loss after RD. HIF-1α cKO in rods altered the responses to retinal detachment for 25 out of 83 HIF-1α target genes that were highly enriched for genes involved in glycolysis. Conclusions Rod-derived HIF-1α plays a key role in the PR response to RD, mediating the transcriptional activity of a battery of genes to promote PR cell survival.
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Affiliation(s)
- Bing X. Ross
- Department of Ophthalmology, University of Michigan Medical School, Kellogg Eye Center, Ann Arbor, Michigan, United States
| | - Lin Jia
- Department of Ophthalmology, University of Michigan Medical School, Kellogg Eye Center, Ann Arbor, Michigan, United States
| | - Dejuan Kong
- Department of Ophthalmology, University of Michigan Medical School, Kellogg Eye Center, Ann Arbor, Michigan, United States
| | - Tiantian Wang
- Department of Ophthalmology, University of Michigan Medical School, Kellogg Eye Center, Ann Arbor, Michigan, United States
- Department of Ophthalmology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Jingyu Yao
- Department of Ophthalmology, University of Michigan Medical School, Kellogg Eye Center, Ann Arbor, Michigan, United States
| | - Heather M. Hager
- Department of Ophthalmology, University of Michigan Medical School, Kellogg Eye Center, Ann Arbor, Michigan, United States
| | - Steven F. Abcouwer
- Department of Ophthalmology, University of Michigan Medical School, Kellogg Eye Center, Ann Arbor, Michigan, United States
| | - David N. Zacks
- Department of Ophthalmology, University of Michigan Medical School, Kellogg Eye Center, Ann Arbor, Michigan, United States
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15
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Chen H, Ma D, Yue F, Qi Y, Dou M, Cui L, Xing Y. The Potential Role of Hypoxia-Inducible Factor-1 in the Progression and Therapy of Central Nervous System Diseases. Curr Neuropharmacol 2022; 20:1651-1666. [PMID: 34325641 PMCID: PMC9881070 DOI: 10.2174/1570159x19666210729123137] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 06/19/2021] [Accepted: 07/16/2021] [Indexed: 11/22/2022] Open
Abstract
Hypoxia-inducible factor-1 (HIF-1) is a heterodimer protein composed of an oxygenregulated functional subunit, HIF-1α, and a structural subunit, HIF-1β, belonging to the basic helixloop- helix family. Strict regulation of HIF-1 protein stability and subsequent transcriptional activity involves various molecular interactions and is primarily controlled by post-transcriptional modifications. Hypoxia, owing to impaired cerebral blood flow, has been implicated in a range of central nervous system (CNS) diseases by exerting a deleterious effect on brain function. As a master oxygen- sensitive transcription regulator, HIF-1 is responsible for upregulating a wide spectrum of target genes involved in glucose metabolism, angiogenesis, and erythropoiesis to generate the adaptive response to avoid, or at least minimize, hypoxic brain injury. However, prolonged, severe oxygen deprivation may directly contribute to the role-conversion of HIF-1, namely, from neuroprotection to the promotion of cell death. Currently, an increasing number of studies support the fact HIF-1 is involved in a variety of CNS-related diseases, such as intracranial atherosclerosis, stroke, and neurodegenerative diseases. This review article chiefly focuses on the effect of HIF-1 on the pathogenesis and mechanism of progression of numerous CNS-related disorders by mediating the expression of various downstream genes and extensive biological functional events and presents robust evidence that HIF-1 may represent a potential therapeutic target for CNS-related diseases.
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Affiliation(s)
- Hongxiu Chen
- Department of Vascular Ultrasonography, Xuanwu Hospital, Capital Medical University, Beijing, China; ,Beijing Diagnostic Center of Vascular Ultrasound, Beijing, China; ,Center of Vascular Ultrasonography, Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical University, 45 Changchun Road, Xicheng District, Beijing, 100053, China; ,Hongxiu Chen and Di Ma contributed equally to this work.
| | - Di Ma
- Department of Neurology, The First Hospital of Jilin University, Changchun, China,Hongxiu Chen and Di Ma contributed equally to this work.
| | - Feixue Yue
- Department of Neurology, The First Hospital of Jilin University, Changchun, China
| | - Yajie Qi
- Department of Neurology, The First Hospital of Jilin University, Changchun, China
| | - Manman Dou
- Department of Neurology, The First Hospital of Jilin University, Changchun, China
| | - Liuping Cui
- Department of Neurology, The First Hospital of Jilin University, Changchun, China
| | - Yingqi Xing
- Department of Vascular Ultrasonography, Xuanwu Hospital, Capital Medical University, Beijing, China; ,Beijing Diagnostic Center of Vascular Ultrasound, Beijing, China; ,Center of Vascular Ultrasonography, Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical University, 45 Changchun Road, Xicheng District, Beijing, 100053, China; ,Address correspondence to this author at the Department of Vascular Ultrasonography, Xuanwu Hospital, Capital Medical University, Beijing Diagnostic Center of Vascular Ultrasound, Center of Vascular Ultrasonography, Beijing Institute of Brain Disorders, 45 Changchun Road, Xicheng District, Beijing, 100053, China; E-mail: This work is recommended by Pro Jiachun Feng, The First Hospital of Jilin University.
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16
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Depletion of HIF-1α by Inducible Cre/loxP Increases the Sensitivity of Cultured Murine Hepatocytes to Ionizing Radiation in Hypoxia. Cells 2022; 11:cells11101671. [PMID: 35626708 PMCID: PMC9139307 DOI: 10.3390/cells11101671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 05/12/2022] [Accepted: 05/15/2022] [Indexed: 02/01/2023] Open
Abstract
The transcription factor hypoxia-inducible factor (HIF) is the main oxygen sensor which regulates adaptation to cellular hypoxia. The aim of this study was to establish cultured murine hepatocyte derived cells (mHDC) as an in vitro model and to analyze the role of HIF-1α in apoptosis induction, DNA damage repair and sensitivity to ionizing radiation (IR). We have crossed C57/BL6 mice that bear loxP sites flanking exon 2 of Hif1a with mice which carry tamoxifen-inducible global Cre expression. From the offspring, we have established transduced hepatocyte cultures which are permanently HIF-1α deficient after tamoxifen treatment. We demonstrated that the cells produce albumin, acetylcholine esterase, and the cytokeratins 8 and 18 which functionally characterizes them as hepatocytes. In moderate hypoxia, HIF-1α deficiency increased IR-induced apoptosis and significantly reduced the surviving fraction of mHDC as compared to HIF-1α expressing cells in colony formation assays. Furthermore, HIF-1α knockout cells displayed increased IR-induced DNA damage as demonstrated by increased generation and persistence of γH2AX foci. HIF-1α deficient cells showed delayed DNA repair after IR in hypoxia in neutral comet assays which may indicate that non-homologous end joining (NHEJ) repair capacity was affected. Overall, our data suggest that HIF-1α inactivation increases radiation sensitivity of mHDC cells.
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17
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Abstract
The regulatory mechanism of hypoxia-inducible factor-1α (HIF-1α) is complex. HIF-1α may inhibit or promote apoptosis in osteoblasts under different physiological conditions, and induce bone regeneration and repair injury in coordination with angiogenesis. The relationship between H2O2 and HIFs is complex, and this study aimed to explore the role of HIF-1α in H2O2-induced apoptosis. Dimethyloxallyl glycine (DMOG) and 2-Methoxyestradiol (2ME) were used to stabilize and inhibit HIFs, respectively. Cell viability was assessed with CCK8. Apoptosis and ROS levels were detected by flow cytometry, and HIF mRNA expression was assessed by reverse transcription-polymerase chain reaction (RT-PCR). Western blot was performed to detect HIF-1α, HIF-2α, Bax, Bak, Bcl-2, Bcl-XL, caspase-9, and PCNA protein amounts. Our data suggest that both HIF-1α and HIF-2α play a protective role in oxidative stress. HIF-1α reduces H2O2-induced apoptosis by upregulating Bcl-2 and Bcl-XL, downregulating Bax, Bak, and caspase-9, stabilizing intracellular ROS levels, and promoting the repair of H2O2-induced DNA damage to reduce apoptosis.
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Affiliation(s)
- Xiaohui Wang
- Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, Nanning, PR China
| | - Lili Wei
- General Geriatrics Division, The First Affiliated Hospital of Guangxi Medical University, Nanning, PR China
| | - Qiaochuan Li
- Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, Nanning, PR China
| | - Yongrong Lai
- Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, Nanning, PR China
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18
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Elucidating the role of hypoxia-inducible factor in rheumatoid arthritis. Inflammopharmacology 2022; 30:737-748. [PMID: 35364736 DOI: 10.1007/s10787-022-00974-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 03/08/2022] [Indexed: 12/12/2022]
Abstract
Rheumatoid arthritis (RA) is a chronic multifactorial disease, provocative, and degenerative autoimmune condition that impacts millions of individuals around the globe. As a result of this understanding, anti-inflammatory drugs have been created, perhaps widely effective (like steroids) and highly specialized methods (including anti-TNF antibody) using biological therapies (including TNF inhibitors). Despite this, the connections between inflammatory response, articular development, and intracellular responsiveness to changes in oxygen concentration are undervalued in rheumatoid arthritis. Hypoxia, or a lack of oxygen, is thought to cause enhanced synovial angiogenesis in RA, which is mediated by some of the hypoxia-inducible factors like vascular endothelial growth factor (VEGF). Substantial genetic alterations occur when the HIF regulatory factors signaling cycle is activated, allowing organelles, tissues, and species to acclimatize to decreasing oxygen saturation. The most well-characterized hypoxia-responsive transcripts are the angiogenic stimulant VEGF, whose production is greatly elevated by hypoxia in several types of cells, especially RA synovium fibroblasts. Blocking vascular endothelial growth factors has been demonstrated to be helpful in murine models of rheumatism, indicating how hypoxia could trigger the angiogenesis process, resulting in the progression of RA. These mechanisms highlight the intimate affiliation amongst hypoxia, angiogenesis, and inflammation in rheumatoid arthritis. This review will look at how hypoxia activates molecular pathways and how other pathways involving inflammatory signals develop and sustain synovitis in rheumatoid arthritis.
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19
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Kurt AH, Ayaz L, Ayaz F, Seferoglu Z, Nural Y. A review on the design, synthesis, and structure-activity relationships of benzothiazole derivatives against hypoxic tumors. Curr Org Synth 2022; 19:772-796. [PMID: 35352663 DOI: 10.2174/1570179419666220330001036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 01/23/2022] [Accepted: 02/11/2022] [Indexed: 12/24/2022]
Abstract
There has been a growing body of studies on benzothiazoles and benzothiazole derivatives as strong and effective antitumor agents against lung, liver, pancreas, breast, and brain tumors. Due to highly proliferative nature of the tumor cells, the oxygen levels get lower than that of a normal tissue in the tumor microenvironment. This situation is called as hypoxia and has been associated with increased ability for carcinogenesis. For the drug design and development strategies, hypoxic nature of the tumor tissues has been exploited more aggressively. Hypoxia itself acts as a signal initiating system to activate the pathways that eventually lead to the spread of the tumor cells into the different tissues, increases the rate of DNA damage and eventually ends up with more mutation levels that may increase the drug resistance. As one of the major mediators of hypoxic response, hypoxia inducible factors (HIFs) has been shown to activate to angiogenesis, metastasis, apoptosis resistance, and many other protumorigenic responses in cancer development. In the current review, we will be discussing the design, synthesis and structure-activity relationships of benzothiazole derivatives against hypoxic tumors such lung, liver, pancreas, breast and brain as potential anticancer drug candidates. The focus points of the study will be the biology behind carcinogenesis and how hypoxia contributes to the process, recent studies on benzothiazole and its derivatives as anti-cancer agents against hypoxic cancers, conclusions and future perspectives. We believe that this review will be useful for the researchers in the field of drug design during their studies to generate novel benzothiazole-containing hybrids against hypoxic tumors with higher efficacies.
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Affiliation(s)
- Akif Hakan Kurt
- Department of Medicinal Pharmacology, Faculty of Medicine, Bolu Abant İzzet Baysal University, 14030, Bolu, Turkey
| | - Lokman Ayaz
- Department of Biochemistry, Faculty of Pharmacy, Trakya University, Edirne, Turkey
| | - Furkan Ayaz
- Department of Biotechnology, Faculty of Arts and Science, Mersin University, 33343, Mersin, Turkey
| | - Zeynel Seferoglu
- Department of Chemistry, Faculty of Science, Gazi University, TR-06500, Ankara, Turkey
| | - Yahya Nural
- Advanced Technology, Research and Application Center, Mersin University, 33343 Mersin, Turkey
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20
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Lappano R, Todd LA, Stanic M, Cai Q, Maggiolini M, Marincola F, Pietrobon V. Multifaceted Interplay between Hormones, Growth Factors and Hypoxia in the Tumor Microenvironment. Cancers (Basel) 2022; 14:539. [PMID: 35158804 PMCID: PMC8833523 DOI: 10.3390/cancers14030539] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/17/2022] [Accepted: 01/18/2022] [Indexed: 02/07/2023] Open
Abstract
Hormones and growth factors (GFs) are signaling molecules implicated in the regulation of a variety of cellular processes. They play important roles in both healthy and tumor cells, where they function by binding to specific receptors on target cells and activating downstream signaling cascades. The stages of tumor progression are influenced by hormones and GF signaling. Hypoxia, a hallmark of cancer progression, contributes to tumor plasticity and heterogeneity. Most solid tumors contain a hypoxic core due to rapid cellular proliferation that outgrows the blood supply. In these circumstances, hypoxia-inducible factors (HIFs) play a central role in the adaptation of tumor cells to their new environment, dramatically reshaping their transcriptional profile. HIF signaling is modulated by a variety of factors including hormones and GFs, which activate signaling pathways that enhance tumor growth and metastatic potential and impair responses to therapy. In this review, we summarize the role of hormones and GFs during cancer onset and progression with a particular focus on hypoxia and the interplay with HIF proteins. We also discuss how hypoxia influences the efficacy of cancer immunotherapy, considering that a hypoxic environment may act as a determinant of the immune-excluded phenotype and a major hindrance to the success of adoptive cell therapies.
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Affiliation(s)
- Rosamaria Lappano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy;
| | - Lauren A. Todd
- Department of Biology, University of Waterloo, Waterloo, ON N2L 3G1, Canada;
| | - Mia Stanic
- Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada;
| | - Qi Cai
- Kite Pharma Inc., Santa Monica, CA 90404, USA; (Q.C.); (F.M.)
| | - Marcello Maggiolini
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy;
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21
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Liu Q, Palmgren VA, Danen EHJ, Le Dévédec SE. Acute vs. chronic vs. intermittent hypoxia in breast Cancer: a review on its application in in vitro research. Mol Biol Rep 2022; 49:10961-10973. [PMID: 36057753 PMCID: PMC9618509 DOI: 10.1007/s11033-022-07802-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Accepted: 07/15/2022] [Indexed: 11/25/2022]
Abstract
Hypoxia has been linked to elevated instances of therapeutic resistance in breast cancer. The exposure of proliferating cancer cells to hypoxia has been shown to induce an aggressive phenotype conducive to invasion and metastasis. Regions of the primary tumors in the breast may be exposed to different types of hypoxia including acute, chronic or intermittent. Intermittent hypoxia (IH), also called cyclic hypoxia, is caused by exposure to cycles of hypoxia and reoxygenation (H-R cycles). Importantly, there is currently no consensus amongst the scientific community on the total duration of hypoxia, the oxygen level, and the possible presence of H-R cycles. In this review, we discuss current methods of hypoxia research, to explore how exposure regimes used in experiments are connected to signaling by different hypoxia inducible factors (HIFs) and to distinct cellular responses in the context of the hallmarks of cancer. We highlight discrepancies in the existing literature on hypoxia research within the field of breast cancer in particular and propose a clear definition of acute, chronic, and intermittent hypoxia based on HIF activation and cellular responses: (i) acute hypoxia is when the cells are exposed for no more than 24 h to an environment with 1% O2 or less; (ii) chronic hypoxia is when the cells are exposed for more than 48 h to an environment with 1% O2 or less and (iii) intermittent hypoxia is when the cells are exposed to at least two rounds of hypoxia (1% O2 or less) separated by at least one period of reoxygenation by exposure to normoxia (8.5% O2 or higher). Our review provides for the first time a guideline for definition of hypoxia related terms and a clear foundation for hypoxia related in vitro (breast) cancer research.
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Affiliation(s)
- Qiuyu Liu
- Division of Drug Discovery and Safety, Leiden Academic Centre of Drug Research, Leiden University, Leiden, The Netherlands
| | - Victoria A.C. Palmgren
- Division of Drug Discovery and Safety, Leiden Academic Centre of Drug Research, Leiden University, Leiden, The Netherlands
| | - Erik HJ Danen
- Division of Drug Discovery and Safety, Leiden Academic Centre of Drug Research, Leiden University, Leiden, The Netherlands
| | - Sylvia E. Le Dévédec
- Division of Drug Discovery and Safety, Leiden Academic Centre of Drug Research, Leiden University, Leiden, The Netherlands
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22
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Wang L, Cao J, Xu Q, Lu X, Yang X, Song Q, Chen S, Du K, Huang R, Zou C. 2-Dodecyl-6-Methoxycyclohexa-2,5-Diene-1,4-Dione Ameliorates Diabetic Cognitive Impairment Through Inhibiting Hif3α and Apoptosis. Front Pharmacol 2021; 12:708141. [PMID: 34975464 PMCID: PMC8716628 DOI: 10.3389/fphar.2021.708141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 11/15/2021] [Indexed: 11/13/2022] Open
Abstract
Diabetes mellitus (DM) is an independent risk factor for cognitive impairment. Although the etiology of diabetic cognitive impairment is complex and multifactorial, the hippocampus neuronal apoptosis is recognized as a main cause of diabetes-induced cognitive impairment. 2-Dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione (DMDD) was purified from the roots of Averrhoa carambola L. Previous research demonstrated that DMDD was safe and effective in delaying some diabetic complications. However, the efficacy of DMDD to ameliorate diabetic cognitive impairment in type 2 diabetes mice has not been reported. In the present study, the behavioral evaluation was performed by Y maze and novel object recognition in db/db mice. Gene expression profiles were detected using mouse lncRNA microarray analysis in the hippocampi of db/db mice. Changes in the neurodegeneration-associated proteins and the apoptosis-related proteins were determined in both db/db mice and high glucose-treated HT22 cells by Western blotting. We observed that DMDD treatment significantly ameliorated the spatial working memory and object recognition memory impairment in db/db mice. Further study showed that neurodegeneration-associated protein tau was decreased after DMDD treatment in the hippocampi of db/db mice. Eleven lncRNAs and four mRNAs including pro-apoptotic gene Hif3a were significantly differently expressed after DMDD treatment in the hippocampi of db/db mice. The expression of Hif3a, cleaved parp, and caspase 3 proteins was significantly increased in the hippocampi of diabetic db/db mice compared with db/m control mice and then decreased after DMDD treatment. Similar beneficial effects of DMDD were observed in HG-treated HT22 cells. These data indicate that DMDD can alleviate cognitive impairment by inhibiting neuronal apoptosis through decreasing the expression of pro-apoptotic protein Hif3a. In conclusion, our study suggests that DMDD has great potential to be a new preventive and therapeutic compound for diabetic cognitive impairment.
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Affiliation(s)
- Lihui Wang
- Key Laboratory of Longevity and Aging-Related Diseases of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, China
- Department of Pharmacology, Guangxi Medical University, Nanning, China
| | - Jinjin Cao
- Key Laboratory of Longevity and Aging-Related Diseases of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, China
| | - Qianqian Xu
- Key Laboratory of Longevity and Aging-Related Diseases of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, China
| | - Xiaomei Lu
- Key Laboratory of Longevity and Aging-Related Diseases of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, China
| | - Xin Yang
- Key Laboratory of Longevity and Aging-Related Diseases of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, China
| | - Qiong Song
- Key Laboratory of Longevity and Aging-Related Diseases of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, China
| | - Shuai Chen
- Key Laboratory of Longevity and Aging-Related Diseases of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, China
| | - Kechen Du
- Key Laboratory of Longevity and Aging-Related Diseases of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, China
| | - Renbin Huang
- Department of Pharmacology, Guangxi Medical University, Nanning, China
- *Correspondence: Renbin Huang, ; Chunlin Zou,
| | - Chunlin Zou
- Key Laboratory of Longevity and Aging-Related Diseases of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, China
- *Correspondence: Renbin Huang, ; Chunlin Zou,
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23
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Kasai S, Li X, Torii S, Yasumoto KI, Sogawa K. Direct protein-protein interaction between Npas4 and IPAS mutually inhibits their critical roles in neuronal cell survival and death. Cell Death Discov 2021; 7:300. [PMID: 34675183 PMCID: PMC8531447 DOI: 10.1038/s41420-021-00690-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 09/17/2021] [Accepted: 10/01/2021] [Indexed: 11/16/2022] Open
Abstract
Inhibitory PAS domain protein (IPAS) is a bifunctional protein that acts as a transcriptional repressor in hypoxia and as a pro-apoptotic protein involved in neuronal cell death. Npas4 (NXF or LE-PAS) is a transcriptional factor that protects nerve cells from endogenous and foreign neurotoxins. Here we show that IPAS and Npas4 antagonize each other through their direct interaction. Coimmunoprecipitation experiments revealed that multiple binding sites on each protein were involved in the interaction. CoCl2 treatment of PC12 cells that induces IPAS repressed the transactivation activity of Npas4, and IPAS siRNA treatment reduced the CoCl2-induced repression. CoCl2-induced apoptosis was suppressed by the addition of KCl that induces Npas4. The protective effect of KCl was attenuated by siRNA-mediated gene silencing of Npas4. Npas4 and IPAS proteins were induced and localized in the cytoplasm of the dopaminergic neurons in the substantia nigra pars compacta after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. Npas4−/− mice exhibited greater sensitivity to MPTP in nigral dopaminergic neurons. Together, these results strongly suggest that neuroprotective activity of Npas4 was, at least partly, exerted by inhibiting the pro-apoptotic activity of IPAS through direct interaction.
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Affiliation(s)
- Shuya Kasai
- Department of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University, Aoba-ku, Sendai, 980-8578, Japan.,Department of Stress Response Science, Center for Advanced Medical Research, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Japan
| | - Xianyu Li
- Department of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University, Aoba-ku, Sendai, 980-8578, Japan
| | - Satoru Torii
- Department of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University, Aoba-ku, Sendai, 980-8578, Japan.,Department of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Ken-Ichi Yasumoto
- Department of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University, Aoba-ku, Sendai, 980-8578, Japan
| | - Kazuhiro Sogawa
- Department of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University, Aoba-ku, Sendai, 980-8578, Japan.
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24
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Breakthrough Science: Hypoxia-Inducible Factors, Oxygen Sensing, and Disorders of Hematopoiesis. Blood 2021; 139:2441-2449. [PMID: 34411243 DOI: 10.1182/blood.2021011043] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 07/28/2021] [Indexed: 11/20/2022] Open
Abstract
Hypoxia-inducible factors (HIF) were discovered as activators of erythropoietin gene transcription in response to reduced O2 availability. O2-dependent hydroxylation of HIFs on proline and asparagine residues regulates protein stability and transcription activity, respectively. Mutations in genes encoding components of the oxygen sensing pathway cause familial erythrocytosis. Several small molecule inhibitors of HIF prolyl hydroxylases are currently in clinical trials as erythropoiesis stimulating agents. HIFs are overexpressed in bone marrow neoplasms, and the development of HIF inhibitors may improve outcome in these disorders.
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25
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Ho JSY, Di Tullio F, Schwarz M, Low D, Incarnato D, Gay F, Tabaglio T, Zhang J, Wollmann H, Chen L, An O, Chan THM, Hall Hickman A, Zheng S, Roudko V, Chen S, Karz A, Ahmed M, He HH, Greenbaum BD, Oliviero S, Serresi M, Gargiulo G, Mann KM, Hernando E, Mulholland D, Marazzi I, Wee DKB, Guccione E. HNRNPM controls circRNA biogenesis and splicing fidelity to sustain cancer cell fitness. eLife 2021; 10:e59654. [PMID: 34075878 PMCID: PMC8346284 DOI: 10.7554/elife.59654] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 05/30/2021] [Indexed: 12/25/2022] Open
Abstract
High spliceosome activity is a dependency for cancer cells, making them more vulnerable to perturbation of the splicing machinery compared to normal cells. To identify splicing factors important for prostate cancer (PCa) fitness, we performed pooled shRNA screens in vitro and in vivo. Our screens identified heterogeneous nuclear ribonucleoprotein M (HNRNPM) as a regulator of PCa cell growth. RNA- and eCLIP-sequencing identified HNRNPM binding to transcripts of key homeostatic genes. HNRNPM binding to its targets prevents aberrant exon inclusion and backsplicing events. In both linear and circular mis-spliced transcripts, HNRNPM preferentially binds to GU-rich elements in long flanking proximal introns. Mimicry of HNRNPM-dependent linear-splicing events using splice-switching-antisense-oligonucleotides was sufficient to inhibit PCa cell growth. This suggests that PCa dependence on HNRNPM is likely a result of mis-splicing of key homeostatic coding and non-coding genes. Our results have further been confirmed in other solid tumors. Taken together, our data reveal a role for HNRNPM in supporting cancer cell fitness. Inhibition of HNRNPM activity is therefore a potential therapeutic strategy in suppressing growth of PCa and other solid tumors.
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Affiliation(s)
- Jessica SY Ho
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR)SingaporeSingapore
- Department of Microbiology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Federico Di Tullio
- Center for Therapeutics Discovery, department of Oncological Sciences and Pharmacological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount SinaiNew YorkUnited States
- Tisch Cancer Institute, Icahn School of Medicine at Mount SinaiNew YorkUnited States
- Department of Oncological Sciences, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Megan Schwarz
- Center for Therapeutics Discovery, department of Oncological Sciences and Pharmacological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount SinaiNew YorkUnited States
- Tisch Cancer Institute, Icahn School of Medicine at Mount SinaiNew YorkUnited States
- Department of Oncological Sciences, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Diana Low
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR)SingaporeSingapore
| | - Danny Incarnato
- IIGM (Italian Institute for Genomic Medicine)TorinoItaly
- Dipartimento di Scienze della Vita e Biologia dei Sistemi Università di TorinoTorinoItaly
- Department of Molecular Genetics, Groningen Biomolecular Sciences and Biotechnology Institute (GBB), University of GroningenGroningenNetherlands
| | - Florence Gay
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR)SingaporeSingapore
| | - Tommaso Tabaglio
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR)SingaporeSingapore
| | - JingXian Zhang
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR)SingaporeSingapore
| | - Heike Wollmann
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR)SingaporeSingapore
| | - Leilei Chen
- Cancer Science Institute of Singapore, National University of SingaporeSingaporeSingapore
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of SingaporeSingaporeSingapore
| | - Omer An
- Cancer Science Institute of Singapore, National University of SingaporeSingaporeSingapore
| | - Tim Hon Man Chan
- Cancer Science Institute of Singapore, National University of SingaporeSingaporeSingapore
| | - Alexander Hall Hickman
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR)SingaporeSingapore
| | - Simin Zheng
- Department of Microbiology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
- NTU Institute of Structural Biology, Nanyang Technological UniversitySingaporeSingapore
| | - Vladimir Roudko
- Tisch Cancer Institute, Icahn School of Medicine at Mount SinaiNew YorkUnited States
- Department of Oncological Sciences, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Sujun Chen
- Department of Medical Biophysics, University of TorontoTorontoCanada
- Princess Margaret Cancer Center, University Health NetworkTorontoCanada
- Ontario Institute for Cancer ResearchTorontoCanada
| | - Alcida Karz
- Interdisciplinary Melanoma Cooperative Group, New York University Langone Medical CenterNew YorkUnited States
- Department of Pathology, New York University Langone Medical CenterNew YorkUnited States
| | - Musaddeque Ahmed
- Princess Margaret Cancer Center, University Health NetworkTorontoCanada
| | - Housheng Hansen He
- Department of Medical Biophysics, University of TorontoTorontoCanada
- Princess Margaret Cancer Center, University Health NetworkTorontoCanada
| | - Benjamin D Greenbaum
- Tisch Cancer Institute, Icahn School of Medicine at Mount SinaiNew YorkUnited States
- Department of Oncological Sciences, Icahn School of Medicine at Mount SinaiNew YorkUnited States
- Department of Medicine, Hematology and Medical Oncology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
- Department of Pathology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Salvatore Oliviero
- IIGM (Italian Institute for Genomic Medicine)TorinoItaly
- Dipartimento di Scienze della Vita e Biologia dei Sistemi Università di TorinoTorinoItaly
| | - Michela Serresi
- Max Delbruck Center for Molecular MedicineBerlin-BuchGermany
| | | | - Karen M Mann
- Department of Molecular Oncology, Moffitt Cancer CenterTampaUnited States
| | - Eva Hernando
- Interdisciplinary Melanoma Cooperative Group, New York University Langone Medical CenterNew YorkUnited States
- Department of Pathology, New York University Langone Medical CenterNew YorkUnited States
| | - David Mulholland
- Tisch Cancer Institute, Icahn School of Medicine at Mount SinaiNew YorkUnited States
- Department of Oncological Sciences, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Ivan Marazzi
- Department of Microbiology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Dave Keng Boon Wee
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR)SingaporeSingapore
| | - Ernesto Guccione
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR)SingaporeSingapore
- Center for Therapeutics Discovery, department of Oncological Sciences and Pharmacological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount SinaiNew YorkUnited States
- Tisch Cancer Institute, Icahn School of Medicine at Mount SinaiNew YorkUnited States
- Department of Oncological Sciences, Icahn School of Medicine at Mount SinaiNew YorkUnited States
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26
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Abstract
The uncontrolled growth of blood vessels is a major pathological factor in human eye diseases that can result in blindness. This effect is termed ocular neovascularization and is seen in diabetic retinopathy, age-related macular degeneration, glaucoma and retinopathy of prematurity. Current treatments for these diseases include laser photocoagulation, topical injection of corticosteroids, intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) agents and vitreoretinal surgery. Although strategies to inhibit VEGF have proved to be dramatically successful in some clinical studies, there remains the possibility of significant adverse effects regarding the blockade of crucial physiological roles of VEGF and the invasive nature of the treatments. Moreover, it is evident that other pro-angiogenic factors also play important roles in the development of these diseases, as seen in cases in which anti-VEGF therapies have failed. Therefore, new types of effective treatments are required. In this review, we discuss a promising strategy for the treatment of ocular neovascular diseases, i.e., the inhibition of hypoxia-inducible factor (HIF), a master regulator of angiogenesis. We also summarize promising recently investigated HIF inhibitors as treatments for ocular diseases. This review will facilitate more comprehensive approaches to understanding the protective aspects of HIF inhibition in the prevention of ocular diseases.
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27
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Chen Y, Gaber T. Hypoxia/HIF Modulates Immune Responses. Biomedicines 2021; 9:biomedicines9030260. [PMID: 33808042 PMCID: PMC8000289 DOI: 10.3390/biomedicines9030260] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 02/23/2021] [Accepted: 02/25/2021] [Indexed: 02/07/2023] Open
Abstract
Oxygen availability varies throughout the human body in health and disease. Under physiological conditions, oxygen availability drops from the lungs over the blood stream towards the different tissues into the cells and the mitochondrial cavities leading to physiological low oxygen conditions or physiological hypoxia in all organs including primary lymphoid organs. Moreover, immune cells travel throughout the body searching for damaged cells and foreign antigens facing a variety of oxygen levels. Consequently, physiological hypoxia impacts immune cell function finally controlling innate and adaptive immune response mainly by transcriptional regulation via hypoxia-inducible factors (HIFs). Under pathophysiological conditions such as found in inflammation, injury, infection, ischemia and cancer, severe hypoxia can alter immune cells leading to dysfunctional immune response finally leading to tissue damage, cancer progression and autoimmunity. Here we summarize the effects of physiological and pathophysiological hypoxia on innate and adaptive immune activity, we provide an overview on the control of immune response by cellular hypoxia-induced pathways with focus on the role of HIFs and discuss the opportunity to target hypoxia-sensitive pathways for the treatment of cancer and autoimmunity.
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Affiliation(s)
- Yuling Chen
- Charité—Universitätsmedizin Berlin, Corporate Ember of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Rheumatology and Clinical Immunology, Charitéplatz 1, 10117 Berlin, Germany;
| | - Timo Gaber
- Charité—Universitätsmedizin Berlin, Corporate Ember of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Rheumatology and Clinical Immunology, Charitéplatz 1, 10117 Berlin, Germany;
- German Rheumatism Research Centre (DRFZ) Berlin, a Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany
- Correspondence: ; Tel.: +49-30-450-513364
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28
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Zhang C, Liu J, Wang J, Zhang T, Xu D, Hu W, Feng Z. The Interplay Between Tumor Suppressor p53 and Hypoxia Signaling Pathways in Cancer. Front Cell Dev Biol 2021; 9:648808. [PMID: 33681231 PMCID: PMC7930565 DOI: 10.3389/fcell.2021.648808] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Accepted: 01/29/2021] [Indexed: 12/13/2022] Open
Abstract
Hypoxia is a hallmark of solid tumors and plays a critical role in different steps of tumor progression, including proliferation, survival, angiogenesis, metastasis, metabolic reprogramming, and stemness of cancer cells. Activation of the hypoxia-inducible factor (HIF) signaling plays a critical role in regulating hypoxic responses in tumors. As a key tumor suppressor and transcription factor, p53 responds to a wide variety of stress signals, including hypoxia, and selectively transcribes its target genes to regulate various cellular responses to exert its function in tumor suppression. Studies have demonstrated a close but complex interplay between hypoxia and p53 signaling pathways. The p53 levels and activities can be regulated by the hypoxia and HIF signaling differently depending on the cell/tissue type and the severity and duration of hypoxia. On the other hand, p53 regulates the hypoxia and HIF signaling at multiple levels. Many tumor-associated mutant p53 proteins display gain-of-function (GOF) oncogenic activities to promote cancer progression. Emerging evidence has also shown that GOF mutant p53 can promote cancer progression through its interplay with the hypoxia and HIF signaling pathway. In this review, we summarize our current understanding of the interplay between the hypoxia and p53 signaling pathways, its impact upon cancer progression, and its potential application in cancer therapy.
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Affiliation(s)
| | | | | | | | | | - Wenwei Hu
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers-State University of New Jersey, New Brunswick, NJ, United States
| | - Zhaohui Feng
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers-State University of New Jersey, New Brunswick, NJ, United States
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29
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Li Y, Liu S, Pan D, Xu B, Xing X, Zhou H, Zhang B, Zhou S, Ning G, Feng S. The potential role and trend of HIF‑1α in intervertebral disc degeneration: Friend or foe? (Review). Mol Med Rep 2021; 23:239. [PMID: 33537810 PMCID: PMC7893690 DOI: 10.3892/mmr.2021.11878] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Accepted: 11/08/2019] [Indexed: 12/11/2022] Open
Abstract
Lower back pain (LBP) is one of the most common reasons for seeking medical advice in orthopedic clinics. Increasingly, research has shown that symptomatic intervertebral disc degeneration (IDD) is mostly related to LBP. This review first outlines the research and findings of studies into IDD, from the physiological structure of the intervertebral disc (IVD) to various pathological cascades. The vicious cycles of IDD are re-described in relation to the analysis of the relationship among the pathological mechanisms involved in IDD. Interestingly, a ‘chief molecule’ was found, hypoxia-inducible factor-1α (HIF-1α), that may regulate all other mechanisms involved in IDD. When the vicious cycle is established, the low oxygen tension activates the expression of HIF-1α, which subsequently enters into the hypoxia-induced HIF pathways. The HIF pathways are dichotomized as friend and foe pathways according to the oxygen tension of the IVD microenvironment. Combined with clinical outcomes and previous research, the trend of IDD development has been predicted in this paper. Lastly, an early precautionary diagnosis and treatment method is proposed whereby nucleus pulposus tissue for biopsy can be obtained through IVD puncture guided by B-ultrasound when the patient is showing symptoms but MRI imaging shows negative results. The assessment criteria for biopsy and the feasibility, superiority and challenges of this approach have been discussed. Overall, it is clear that HIF-1α is an indispensable reference indicator for the accurate diagnosis and treatment of IDD.
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Affiliation(s)
- Yongjin Li
- Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Shen Liu
- Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Dayu Pan
- Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Baoshan Xu
- Department of Spine Surgery, Tianjin Hospital, Tianjin 300000, P.R. China
| | - Xuewu Xing
- Department of Orthopedic Surgery, First Central Clinical of Tianjin Medical University, Tianjin 300052, P.R. China
| | - Hengxing Zhou
- Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Bin Zhang
- Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Suzhe Zhou
- Department of Orthopedics, The Affiliated Zhongshan Hospital of Fudan University, Shanghai 200034, P.R. China
| | - Guangzhi Ning
- Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Shiqing Feng
- Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
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30
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Abstract
Over the last few years, cancer immunotherapy experienced tremendous developments and it is nowadays considered a promising strategy against many types of cancer. However, the exclusion of lymphocytes from the tumor nest is a common phenomenon that limits the efficiency of immunotherapy in solid tumors. Despite several mechanisms proposed during the years to explain the immune excluded phenotype, at present, there is no integrated understanding about the role played by different models of immune exclusion in human cancers. Hypoxia is a hallmark of most solid tumors and, being a multifaceted and complex condition, shapes in a unique way the tumor microenvironment, affecting gene transcription and chromatin remodeling. In this review, we speculate about an upstream role for hypoxia as a common biological determinant of immune exclusion in solid tumors. We also discuss the current state of ex vivo and in vivo imaging of hypoxic determinants in relation to T cell distribution that could mechanisms of immune exclusion and discover functional-morphological tumor features that could support clinical monitoring.
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31
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Elzakra N, Kim Y. HIF-1α Metabolic Pathways in Human Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1280:243-260. [PMID: 33791987 DOI: 10.1007/978-3-030-51652-9_17] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Oxygen is directly involved in many key pathophysiological processes. Oxygen deficiency, also known as hypoxia, could have adverse effects on mammalian cells, with ischemia in vital tissues being the most significant (Michiels C. Physiological and pathological responses to hypoxia. Am J Pathol 164(6): 1875-1882, 2004); therefore, timely adaptive responses to variations in oxygen availability are essential for cellular homeostasis and survival. The most critical molecular event in hypoxic response is the activation and stabilization of a transcriptional factor termed hypoxia-induced factor-1 (HIF-1) that is responsible for the upregulation of many downstream effector genes, collectively known as hypoxia-responsive genes. Multiple key biological pathways such as proliferation, energy metabolism, invasion, and metastasis are governed by these genes; thus, HIF-1-mediated pathways are equally pivotal in both physiology and pathology.As we gain knowledge on the molecular mechanisms underlying the regulation of HIF-1, a great focus has been placed on elucidating the cellular function of HIF-1, particularly the role of HIF-1 in cancer pathogenesis pathways such as proliferation, invasion, angiogenesis, and metastasis. In cancer, HIF-1 is directly involved in the shift of cancer tissues from oxidative phosphorylation to aerobic glycolysis, a phenomenon known as the Warburg effect. Although targeting HIF-1 as a cancer therapy seems like an extremely rational approach, owing to the complex network of its downstream effector genes, the development of specific HIF-1 inhibitors with fewer side effects and more specificity has not been achieved. Therefore, in this review, we provide a brief background about the function of HIF proteins in hypoxia response with a special emphasis on the unique role played by HIF-1α in cancer growth and invasiveness, in the hypoxia response context.
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Affiliation(s)
- Naseim Elzakra
- School of Dentistry, University of California Los Angeles, Los Angeles, CA, USA.
| | - Yong Kim
- School of Dentistry, University of California Los Angeles, Los Angeles, CA, USA. .,Laboratory of Stem Cell and Cancer Epigenetics, Center for Oral Oncology Research, UCLA School of Dentistry, Los Angeles, CA, USA. .,UCLA's Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA. .,Broad Stem Cell Research Institute, Los Angeles, CA, USA.
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32
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Albanese A, Daly LA, Mennerich D, Kietzmann T, Sée V. The Role of Hypoxia-Inducible Factor Post-Translational Modifications in Regulating Its Localisation, Stability, and Activity. Int J Mol Sci 2020; 22:E268. [PMID: 33383924 PMCID: PMC7796330 DOI: 10.3390/ijms22010268] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 12/22/2020] [Accepted: 12/23/2020] [Indexed: 12/12/2022] Open
Abstract
The hypoxia signalling pathway enables adaptation of cells to decreased oxygen availability. When oxygen becomes limiting, the central transcription factors of the pathway, hypoxia-inducible factors (HIFs), are stabilised and activated to induce the expression of hypoxia-regulated genes, thereby maintaining cellular homeostasis. Whilst hydroxylation has been thoroughly described as the major and canonical modification of the HIF-α subunits, regulating both HIF stability and activity, a range of other post-translational modifications decorating the entire protein play also a crucial role in altering HIF localisation, stability, and activity. These modifications, their conservation throughout evolution, and their effects on HIF-dependent signalling are discussed in this review.
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Affiliation(s)
- Adam Albanese
- Department of Molecular Physiology and Cell Signalling, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L697ZB, UK;
| | - Leonard A. Daly
- Department of Biochemistry and System Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L697ZB, UK;
| | - Daniela Mennerich
- Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, FI-90014 Oulu, Finland; (D.M.); (T.K.)
| | - Thomas Kietzmann
- Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, FI-90014 Oulu, Finland; (D.M.); (T.K.)
| | - Violaine Sée
- Department of Molecular Physiology and Cell Signalling, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L697ZB, UK;
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33
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Vilys L, Peciuliene I, Jakubauskiene E, Zinkeviciute R, Makino Y, Kanopka A. U2AF - Hypoxia-induced fas alternative splicing regulator. Exp Cell Res 2020; 399:112444. [PMID: 33347855 DOI: 10.1016/j.yexcr.2020.112444] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 12/01/2020] [Accepted: 12/15/2020] [Indexed: 01/21/2023]
Abstract
The splicing machinery heavily contributes to biological complexity and especially to the ability of cells to adapt to altered cellular conditions. Hypoxia also plays a key role in the pathophysiology of many disease states. Recent studies have revealed that tumorigenesis and hypoxia are involved in large-scale alterations in alternative pre-mRNA splicing. Fas pre-mRNA is alternatively spliced by excluding exon 6 to produce soluble Fas (sFas) protein that lacks a transmembrane domain and acts by inhibiting Fas mediated apoptosis. In the present study we show that U2AF is involved in hypoxia dependent anti-apoptotic Fas mRNA isoform formation. Our performed studies show that U2AF-RNA interaction is reduced in hypoxic cells, leading to reduction of Fas and increased sFas mRNAs formation. Efficient U2AF-RNA interactions of both subunits are important for Fas exon 6 inclusion into forming mRNA in normoxic and hypoxic cells.
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Affiliation(s)
- Laurynas Vilys
- Department of Immunology and Cell Biology, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Inga Peciuliene
- Department of Immunology and Cell Biology, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Egle Jakubauskiene
- Department of Immunology and Cell Biology, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Ruta Zinkeviciute
- Department of Eukaryote Gene Engineering, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Yuichi Makino
- Division of Metabolism and Biosystemic Science, Department of Medicine, Asahikawa Medical College, Asahikawa, Hokkaido, Japan
| | - Arvydas Kanopka
- Department of Immunology and Cell Biology, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania.
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Xu Z, Wei J, Qin F, Sun Y, Xiang W, Yuan L, Qin J, Deng K, Zheng T, Li S. Hypoxia-associated alternative splicing signature in lung adenocarcinoma. Epigenomics 2020; 13:47-63. [PMID: 33336585 DOI: 10.2217/epi-2020-0399] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Aim: To establish a signature based on hypoxia-related alternative splicing (AS) events for lung adenocarcinoma. Materials & methods: The least absolute shrinkage and selection operator Cox approach was used to construct a prognostic model. A nomogram that integrates the final AS predictor and stage was created. The network of the key AS events and splicing factors was created. Results: We created a prognostic signature of 11 AS events. Moreover, a nomogram that constitutes the pathological stage and risk was exhibited to be greatly effective in estimating the survival likelihood of lung adenocarcinoma patients. Conclusion: Herein we developed the first-ever signature based on hypoxia-related AS events with both prognostic predictive power and diagnostic efficacy.
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Affiliation(s)
- Zhanyu Xu
- Department of Thoracic & Cardiovascular Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, PR China
| | - Jiangbo Wei
- Department of Thoracic & Cardiovascular Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, PR China
| | - Fanglu Qin
- Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, PR China
| | - Yu Sun
- Department of Thoracic & Cardiovascular Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, PR China
| | - Weiwei Xiang
- Department of Thoracic & Cardiovascular Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, PR China
| | - Liqiang Yuan
- Department of Thoracic & Cardiovascular Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, PR China
| | - Junqi Qin
- Department of Thoracic & Cardiovascular Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, PR China
| | - Kun Deng
- Department of Thoracic & Cardiovascular Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, PR China
| | - Tiaozhan Zheng
- Department of Thoracic & Cardiovascular Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, PR China
| | - Shikang Li
- Department of Thoracic & Cardiovascular Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, PR China
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Li RL, He LY, Zhang Q, Liu J, Lu F, Duan HXY, Fan LH, Peng W, Huang YL, Wu CJ. HIF-1α is a Potential Molecular Target for Herbal Medicine to Treat Diseases. DRUG DESIGN DEVELOPMENT AND THERAPY 2020; 14:4915-4949. [PMID: 33235435 PMCID: PMC7680173 DOI: 10.2147/dddt.s274980] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 10/22/2020] [Indexed: 12/12/2022]
Abstract
HIF-1α is an important factor regulating oxygen balance in mammals, and its expression is closely related to various physiological and pathological conditions of the body. Because HIF-1α plays an important role in the occurrence and development of cancer and other diseases, it has become an enduring research hotspot. At the same time, natural medicines and traditional Chinese medicine compounds have amazing curative effects in various diseases related to HIF-1 subtype due to their unique pharmacological effects and more effective ingredients. Therefore, in this article, we first outline the structure of HIF-1α and the regulation related to its expression, then introduce various diseases closely related to HIF-1α, and finally focus on the regulation of natural medicines and compound Chinese medicines through various pathways. This will help us understand HIF-1α systematically, and use HIF-1α as a target to discover more natural medicines and traditional Chinese medicines that can treat related diseases.
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Affiliation(s)
- Ruo-Lan Li
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, People's Republic of China
| | - Li-Ying He
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, People's Republic of China
| | - Qing Zhang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, People's Republic of China
| | - Jia Liu
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, People's Republic of China
| | - Feng Lu
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, People's Republic of China
| | - Hu-Xin-Yue Duan
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, People's Republic of China
| | - Lin-Hong Fan
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, People's Republic of China
| | - Wei Peng
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, People's Republic of China
| | - Yong-Liang Huang
- Pharmacy Department, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, People's Republic of China
| | - Chun-Jie Wu
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, People's Republic of China
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36
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Saxena K, Jolly MK, Balamurugan K. Hypoxia, partial EMT and collective migration: Emerging culprits in metastasis. Transl Oncol 2020; 13:100845. [PMID: 32781367 PMCID: PMC7419667 DOI: 10.1016/j.tranon.2020.100845] [Citation(s) in RCA: 131] [Impact Index Per Article: 26.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 07/12/2020] [Accepted: 07/27/2020] [Indexed: 02/07/2023] Open
Abstract
Epithelial-mesenchymal transition (EMT) is a cellular biological process involved in migration of primary cancer cells to secondary sites facilitating metastasis. Besides, EMT also confers properties such as stemness, drug resistance and immune evasion which can aid a successful colonization at the distant site. EMT is not a binary process; recent evidence suggests that cells in partial EMT or hybrid E/M phenotype(s) can have enhanced stemness and drug resistance as compared to those undergoing a complete EMT. Moreover, partial EMT enables collective migration of cells as clusters of circulating tumor cells or emboli, further endorsing that cells in hybrid E/M phenotypes may be the 'fittest' for metastasis. Here, we review mechanisms and implications of hybrid E/M phenotypes, including their reported association with hypoxia. Hypoxia-driven activation of HIF-1α can drive EMT. In addition, cyclic hypoxia, as compared to acute or chronic hypoxia, shows the highest levels of active HIF-1α and can augment cancer aggressiveness to a greater extent, including enriching for a partial EMT phenotype. We also discuss how metastasis is influenced by hypoxia, partial EMT and collective cell migration, and call for a better understanding of interconnections among these mechanisms. We discuss the known regulators of hypoxia, hybrid EMT and collective cell migration and highlight the gaps which needs to be filled for connecting these three axes which will increase our understanding of dynamics of metastasis and help control it more effectively.
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Affiliation(s)
- Kritika Saxena
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India
| | - Mohit Kumar Jolly
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India.
| | - Kuppusamy Balamurugan
- Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.
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37
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Hypoxia and Oxygen-Sensing Signaling in Gene Regulation and Cancer Progression. Int J Mol Sci 2020; 21:ijms21218162. [PMID: 33142830 PMCID: PMC7663541 DOI: 10.3390/ijms21218162] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 10/28/2020] [Accepted: 10/29/2020] [Indexed: 12/19/2022] Open
Abstract
Oxygen homeostasis regulation is the most fundamental cellular process for adjusting physiological oxygen variations, and its irregularity leads to various human diseases, including cancer. Hypoxia is closely associated with cancer development, and hypoxia/oxygen-sensing signaling plays critical roles in the modulation of cancer progression. The key molecules of the hypoxia/oxygen-sensing signaling include the transcriptional regulator hypoxia-inducible factor (HIF) which widely controls oxygen responsive genes, the central members of the 2-oxoglutarate (2-OG)-dependent dioxygenases, such as prolyl hydroxylase (PHD or EglN), and an E3 ubiquitin ligase component for HIF degeneration called von Hippel–Lindau (encoding protein pVHL). In this review, we summarize the current knowledge about the canonical hypoxia signaling, HIF transcription factors, and pVHL. In addition, the role of 2-OG-dependent enzymes, such as DNA/RNA-modifying enzymes, JmjC domain-containing enzymes, and prolyl hydroxylases, in gene regulation of cancer progression, is specifically reviewed. We also discuss the therapeutic advancement of targeting hypoxia and oxygen sensing pathways in cancer.
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38
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Todd VM, Johnson RW. Hypoxia in bone metastasis and osteolysis. Cancer Lett 2020; 489:144-154. [PMID: 32561416 PMCID: PMC7429356 DOI: 10.1016/j.canlet.2020.06.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Revised: 05/15/2020] [Accepted: 06/01/2020] [Indexed: 12/19/2022]
Abstract
Hypoxia is a common feature in tumors, driving pathways that promote epithelial-to-mesenchymal transition, invasion, and metastasis. Clinically, high levels of hypoxia-inducible factor (HIF) expression and stabilization at the primary site in many cancer types is associated with poor patient outcomes. Experimental evidence suggests that HIF signaling in the primary tumor promotes their dissemination to the bone, as well as the release of factors such as LOX that act distantly on the bone to stimulate osteolysis and form a pre-metastatic niche. Additionally, the bone itself is a generally hypoxic organ, fueling the activation of HIF signaling in bone resident cells, promoting tumor cell homing to the bone as well as osteoclastogenesis. The hypoxic microenvironment of the bone also stimulates the vicious cycle of tumor-induced bone destruction, further fueling tumor cell growth and osteolysis. Furthermore, hypoxia appears to regulate key tumor dormancy factors. Thus, hypoxia acts both on the tumor cells as well as the metastatic site to promote tumor cell metastasis.
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Affiliation(s)
- Vera M Todd
- Graduate Program in Cancer Biology, Vanderbilt University, Nashville, TN, USA; Vanderbilt Center for Bone Biology, Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Rachelle W Johnson
- Graduate Program in Cancer Biology, Vanderbilt University, Nashville, TN, USA; Vanderbilt Center for Bone Biology, Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.
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39
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Tolonen JP, Heikkilä M, Malinen M, Lee HM, Palvimo JJ, Wei GH, Myllyharju J. A long hypoxia-inducible factor 3 isoform 2 is a transcription activator that regulates erythropoietin. Cell Mol Life Sci 2020; 77:3627-3642. [PMID: 31768607 PMCID: PMC7452874 DOI: 10.1007/s00018-019-03387-9] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 11/12/2019] [Accepted: 11/15/2019] [Indexed: 12/19/2022]
Abstract
Hypoxia-inducible factor (HIF), an αβ dimer, is the master regulator of oxygen homeostasis with hundreds of hypoxia-inducible target genes. Three HIF isoforms differing in the oxygen-sensitive α subunit exist in vertebrates. While HIF-1 and HIF-2 are known transcription activators, HIF-3 has been considered a negative regulator of the hypoxia response pathway. However, the human HIF3A mRNA is subject to complex alternative splicing. It was recently shown that the long HIF-3α variants can form αβ dimers that possess transactivation capacity. Here, we show that overexpression of the long HIF-3α2 variant induces the expression of a subset of genes, including the erythropoietin (EPO) gene, while simultaneous downregulation of all HIF-3α variants by siRNA targeting a shared HIF3A region leads to downregulation of EPO and additional genes. EPO mRNA and protein levels correlated with HIF3A silencing and HIF-3α2 overexpression. Chromatin immunoprecipitation analyses showed that HIF-3α2 binding associated with canonical hypoxia response elements in the promoter regions of EPO. Luciferase reporter assays showed that the identified HIF-3α2 chromatin-binding regions were sufficient to promote transcription by all three HIF-α isoforms. Based on these data, HIF-3α2 is a transcription activator that directly regulates EPO expression.
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Affiliation(s)
- Jussi-Pekka Tolonen
- Oulu Center for Cell-Matrix Research, University of Oulu, PO Box 5400, 90014, Oulu, Finland
- Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, 90014, Oulu, Finland
| | - Minna Heikkilä
- Oulu Center for Cell-Matrix Research, University of Oulu, PO Box 5400, 90014, Oulu, Finland
- Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, 90014, Oulu, Finland
| | - Marjo Malinen
- Department of Environmental and Biological Sciences, University of Eastern Finland, 80100, Joensuu, Finland
| | - Hang-Mao Lee
- Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, 90014, Oulu, Finland
| | - Jorma J Palvimo
- Institute of Biomedicine, University of Eastern Finland, 70211, Kuopio, Finland
| | - Gong-Hong Wei
- Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, 90014, Oulu, Finland
| | - Johanna Myllyharju
- Oulu Center for Cell-Matrix Research, University of Oulu, PO Box 5400, 90014, Oulu, Finland.
- Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, 90014, Oulu, Finland.
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40
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Abstract
The oxygen levels organ and tissue microenvironments vary depending on the distance of their vasculature from the left ventricle of the heart. For instance, the oxygen levels of lymph nodes and the spleen are significantly lower than that in atmospheric air. Cellular detection of oxygen and their response to low oxygen levels can exert a significant impact on virus infection. Generally, viruses that naturally infect well-oxygenated organs are less able to infect cells under hypoxic conditions. Conversely, viruses that infect organs under lower oxygen tensions thrive under hypoxic conditions. This suggests that in vitro experiments performed exclusively under atmospheric conditions ignores oxygen-induced modifications in both host and viral responses. Here, we review the mechanisms of how cells adapt to low oxygen tensions and its impact on viral infections. With growing evidence supporting the role of oxygen microenvironments in viral infections, this review highlights the importance of factoring oxygen concentrations into in vitro assay conditions. Bridging the gap between in vitro and in vivo oxygen tensions would allow for more physiologically representative insights into viral pathogenesis.
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Affiliation(s)
- Esther Shuyi Gan
- Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore.
| | - Eng Eong Ooi
- Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore.,Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore.,Department of Microbiology and Immunology, National University of Singapore, Singapore, Singapore
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41
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Sadeghi F, Kardar GA, Bolouri MR, Nasri F, Sadri M, Falak R. Overexpression of bHLH domain of HIF-1 failed to inhibit the HIF-1 transcriptional activity in hypoxia. Biol Res 2020; 53:25. [PMID: 32503642 PMCID: PMC7275393 DOI: 10.1186/s40659-020-00293-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 05/18/2020] [Indexed: 01/22/2023] Open
Abstract
Background Hypoxia inducible factor-1 (HIF-1) is considered as the most activated transcriptional factor in response to low oxygen level or hypoxia. HIF-1 binds the hypoxia response element (HRE) sequence in the promoter of different genes, mainly through the bHLH domain and activates the transcription of genes, especially those involved in angiogenesis and EMT. Considering the critical role of bHLH in binding HIF-1 to the HRE sequence, we hypothesized that bHLH could be a promising candidate to be targeted in hypoxia condition. Methods We inserted an inhibitory bHLH (ibHLH) domain in a pIRES2-EGFP vector and transfected HEK293T cells with either the control vector or the designed construct. The ibHLH domain consisted of bHLH domains of both HIF-1a and Arnt, capable of competing with HIF-1 in binding to HRE sequences. The transfected cells were then treated with 200 µM of cobalt chloride (CoCl2) for 48 h to induce hypoxia. Real-time PCR and western blot were performed to evaluate the effect of ibHLH on the genes and proteins involved in angiogenesis and EMT. Results Hypoxia was successfully induced in the HEK293T cell line as the gene expression of VEGF, vimentin, and β-catenin were significantly increased after treatment of untransfected HEK293T cells with 200 µM CoCl2. The gene expression of VEGF, vimentin, and β-catenin and protein level of β-catenin were significantly decreased in the cells transfected with either control or ibHLH vectors in hypoxia. However, ibHLH failed to be effective on these genes and the protein level of β-catenin, when compared to the control vector. We also observed that overexpression of ibHLH had more inhibitory effect on gene and protein expression of N-cadherin compared to the control vector. However, it was not statistically significant. Conclusion bHLH has been reported to be an important domain involved in the DNA binding activity of HIF. However, we found that targeting this domain is not sufficient to inhibit the endogenous HIF-1 transcriptional activity. Further studies about the function of critical domains of HIF-1 are necessary for developing a specific HIF-1 inhibitor.
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Affiliation(s)
- Fatemeh Sadeghi
- Immunology Research Center, Iran University of Medical Sciences, Tehran, Iran.,Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Gholam Ali Kardar
- Immunology Asthma & Allergy Research Institute, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
| | - Mohammad Reza Bolouri
- Immunology Research Center, Iran University of Medical Sciences, Tehran, Iran.,Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Farzad Nasri
- Immunology Research Center, Iran University of Medical Sciences, Tehran, Iran.,Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Maryam Sadri
- Immunology Research Center, Iran University of Medical Sciences, Tehran, Iran.,Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Reza Falak
- Immunology Research Center, Iran University of Medical Sciences, Tehran, Iran. .,Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
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Xiong Q, Liu B, Ding M, Zhou J, Yang C, Chen Y. Hypoxia and cancer related pathology. Cancer Lett 2020; 486:1-7. [PMID: 32439418 DOI: 10.1016/j.canlet.2020.05.002] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 04/18/2020] [Accepted: 05/05/2020] [Indexed: 12/15/2022]
Abstract
Hypoxic environments occur normally at high altitude, or in underground burrows and in deep sea habitats. They also occur pathologically in human ischemia and in hypoxic solid tumors. Hypoxia in various cancer types and its related molecular mechanisms are associated with a poor clinical outcome. This review will discuss how hypoxia can influence two aspects of tumorigenesis, namely the direct, cell-intrinsic oncogenic effects, as well as the indirect effects on tumor progression mediated by an altered tumor microenvironment. We will also discuss recent progress in identifying the functional roles of hypoxia-related factors (HIFs), along with their regulators and downstream target genes, in cancer stem cells and therapy. Importantly, we propose, using convergent evolution schemes to identify novel biomarkers for both hypoxia adaptation and hypoxic solid tumors as an important strategy in the future.
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Affiliation(s)
- Qiuxia Xiong
- Department of Clinical Laboratory, the First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China; Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China
| | - Baiyang Liu
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Mingxia Ding
- Deparment of Urology, the Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, China
| | - Jumin Zhou
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China
| | - Cuiping Yang
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China.
| | - Yongbin Chen
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China; Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, Yunnan, 650223, China.
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43
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Kuo TC, Kung HJ, Shih JW. Signaling in and out: long-noncoding RNAs in tumor hypoxia. J Biomed Sci 2020; 27:59. [PMID: 32370770 PMCID: PMC7201962 DOI: 10.1186/s12929-020-00654-x] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 04/22/2020] [Indexed: 02/07/2023] Open
Abstract
Over the past few years, long non-coding RNAs (lncRNAs) are recognized as key regulators of gene expression at chromatin, transcriptional and posttranscriptional level with pivotal roles in various biological and pathological processes, including cancer. Hypoxia, a common feature of the tumor microenvironment, profoundly affects gene expression and is tightly associated with cancer progression. Upon tumor hypoxia, the central regulator HIF (hypoxia-inducible factor) is upregulated and orchestrates transcription reprogramming, contributing to aggressive phenotypes in numerous cancers. Not surprisingly, lncRNAs are also transcriptional targets of HIF and serve as effectors of hypoxia response. Indeed, the number of hypoxia-associated lncRNAs (HALs) identified has risen sharply, illustrating the expanding roles of lncRNAs in hypoxia signaling cascade and responses. Moreover, through extra-cellular vesicles, lncRNAs could transmit hypoxia responses between cancer cells and the associated microenvironment. Notably, the aberrantly expressed cellular or exosomal HALs can serve as potential prognostic markers and therapeutic targets. In this review, we provide an update of the current knowledge about the expression, involvement and potential clinical impact of lncRNAs in tumor hypoxia, with special focus on their unique molecular regulation of HIF cascade and hypoxia-induced malignant progression.
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Affiliation(s)
- Tse-Chun Kuo
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli County, 35053, Taiwan, ROC
| | - Hsing-Jien Kung
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli County, 35053, Taiwan, ROC.,Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan, ROC.,Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan, ROC.,Department of Biochemistry and Molecular Medicine, Comprehensive Cancer Center, University of California at Davis, Sacramento, CA, 95817, USA.,TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, 110, Taiwan, ROC
| | - Jing-Wen Shih
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan, ROC. .,Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan, ROC. .,TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, 110, Taiwan, ROC. .,Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan, ROC.
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44
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Guo Y, Xiao Z, Yang L, Gao Y, Zhu Q, Hu L, Huang D, Xu Q. Hypoxia‑inducible factors in hepatocellular carcinoma (Review). Oncol Rep 2019; 43:3-15. [PMID: 31746396 PMCID: PMC6908932 DOI: 10.3892/or.2019.7397] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Accepted: 08/16/2019] [Indexed: 12/12/2022] Open
Abstract
Maintenance of an appropriate oxygen concentration is essential for the function of the liver. However, in many pathological conditions, and particularly in the tumor microenvironment, cells and tissues are frequently in a hypoxic state. In the presence of hypoxia, the cells adapt to the low oxygen levels through the hypoxia-inducible factor (HIF) pathway. Overgrowth of tumor cells restricts the diffusion of oxygen in tumors, leading to insufficient blood supply and the creation of a hypoxic microenvironment, and, as a consequence, activation of the expression of HIFs. HIFs possess a wide range of target genes, which function to control a variety of signaling pathways; thus, HIFs modulate cellular metabolism, immune escape, angiogenesis, metastasis, extracellular matrix remodeling, cancer stem cells and other properties of the tumor. Given their crucial role in the occurrence and development of tumors, HIFs are expected to become new targets of precise treatment of hepatocellular carcinoma.
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Affiliation(s)
- Yang Guo
- Graduate Department, BengBu Medical College, Bengbu, Anhui 233030, P.R. China
| | - Zunqiang Xiao
- The Second Clinical Medical Department, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310014, P.R. China
| | - Liu Yang
- The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang 310014, P.R. China
| | - Yuling Gao
- Department of Genetics, Shaoxing Women and Children Hospital, Shaoxin, Zhejiang 312030, P.R. China
| | - Qiaojuan Zhu
- The Second Clinical Medical Department, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310014, P.R. China
| | - Linjun Hu
- Medical Department, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Dongsheng Huang
- The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang 310014, P.R. China
| | - Qiuran Xu
- The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang 310014, P.R. China
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45
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Mennerich D, Kubaichuk K, Kietzmann T. DUBs, Hypoxia, and Cancer. Trends Cancer 2019; 5:632-653. [PMID: 31706510 DOI: 10.1016/j.trecan.2019.08.005] [Citation(s) in RCA: 155] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 08/24/2019] [Accepted: 08/27/2019] [Indexed: 02/08/2023]
Abstract
Alterations in protein ubiquitylation and hypoxia are commonly associated with cancer. Ubiquitylation is carried out by three sequentially acting ubiquitylating enzymes and can be opposed by deubiquitinases (DUBs), which have emerged as promising drug targets. Apart from protein localization and activity, ubiquitylation regulates degradation of proteins, among them hypoxia-inducible factors (HIFs). Thereby, various E3 ubiquitin ligases and DUBs regulate HIF abundance. Conversely, several E3s and DUBs are regulated by hypoxia. While hypoxia is a powerful HIF regulator, less is known about hypoxia-regulated DUBs and their impact on HIFs. Here, we review current knowledge about the relationship of E3s, DUBs, and hypoxia signaling. We also discuss the reciprocal regulation of DUBs by hypoxia and use of DUB-specific drugs in cancer.
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Affiliation(s)
- Daniela Mennerich
- Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, 90570, Finland
| | - Kateryna Kubaichuk
- Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, 90570, Finland
| | - Thomas Kietzmann
- Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, 90570, Finland; Biocenter Oulu, University of Oulu, Oulu, 90570, Finland.
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46
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Shibuya T, Iinuma S, Honma M, Makino Y, Ishida-Yamamoto A. Psoriasis-like skin inflammation is reduced in transgenic mice overexpressing inhibitory PAS domain protein. J Dermatol 2019; 46:1219-1221. [PMID: 31583736 DOI: 10.1111/1346-8138.15105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Accepted: 09/05/2019] [Indexed: 11/30/2022]
Affiliation(s)
- Takashi Shibuya
- Department of Dermatology, Asahikawa Medical University, Asahikawa, Japan
| | - Shin Iinuma
- Department of Dermatology, Asahikawa Medical University, Asahikawa, Japan
| | - Masaru Honma
- Department of Dermatology, Asahikawa Medical University, Asahikawa, Japan
| | - Yuichi Makino
- Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan
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47
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Shemarova IV, Nesterov VP. Molecular Basis of Cardioprotection in Ischemic Heart Disease. J EVOL BIOCHEM PHYS+ 2019. [DOI: 10.1134/s0022093019030013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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48
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Saxena K, Jolly MK. Acute vs. Chronic vs. Cyclic Hypoxia: Their Differential Dynamics, Molecular Mechanisms, and Effects on Tumor Progression. Biomolecules 2019; 9:E339. [PMID: 31382593 PMCID: PMC6722594 DOI: 10.3390/biom9080339] [Citation(s) in RCA: 129] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 07/31/2019] [Accepted: 08/01/2019] [Indexed: 02/07/2023] Open
Abstract
Hypoxia has been shown to increase the aggressiveness and severity of tumor progression. Along with chronic and acute hypoxic regions, solid tumors contain regions of cycling hypoxia (also called intermittent hypoxia or IH). Cyclic hypoxia is mimicked in vitro and in vivo by periodic exposure to cycles of hypoxia and reoxygenation (H-R cycles). Compared to chronic hypoxia, cyclic hypoxia has been shown to augment various hallmarks of cancer to a greater extent: angiogenesis, immune evasion, metastasis, survival etc. Cycling hypoxia has also been shown to be the major contributing factor in increasing the risk of cancer in obstructive sleep apnea (OSA) patients. Here, we first compare and contrast the effects of acute, chronic and intermittent hypoxia in terms of molecular pathways activated and the cellular processes affected. We highlight the underlying complexity of these differential effects and emphasize the need to investigate various combinations of factors impacting cellular adaptation to hypoxia: total duration of hypoxia, concentration of oxygen (O2), and the presence of and frequency of H-R cycles. Finally, we summarize the effects of cycling hypoxia on various hallmarks of cancer highlighting their dependence on the abovementioned factors. We conclude with a call for an integrative and rigorous analysis of the effects of varying extents and durations of hypoxia on cells, including tools such as mechanism-based mathematical modelling and microfluidic setups.
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Affiliation(s)
- Kritika Saxena
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore, 560012, India
| | - Mohit Kumar Jolly
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore, 560012, India.
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49
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Nakayama K, Kataoka N. Regulation of Gene Expression under Hypoxic Conditions. Int J Mol Sci 2019; 20:ijms20133278. [PMID: 31277312 PMCID: PMC6651685 DOI: 10.3390/ijms20133278] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Revised: 06/28/2019] [Accepted: 07/02/2019] [Indexed: 02/07/2023] Open
Abstract
Eukaryotes are often subjected to different kinds of stress. In order to adjust to such circumstances, eukaryotes activate stress–response pathways and regulate gene expression. Eukaryotic gene expression consists of many different steps, including transcription, RNA processing, RNA transport, and translation. In this review article, we focus on both transcriptional and post-transcriptional regulations of gene expression under hypoxic conditions. In the first part of the review, transcriptional regulations mediated by various transcription factors including Hypoxia-Inducible Factors (HIFs) are described. In the second part, we present RNA splicing regulations under hypoxic conditions, which are mediated by splicing factors and their kinases. This work summarizes and discusses the emerging studies of those two gene expression machineries under hypoxic conditions.
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Affiliation(s)
- Koh Nakayama
- Oxygen Biology Laboratory, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo 113-8510, Japan.
| | - Naoyuki Kataoka
- Laboratory of Cell Regulation, Departments of Applied Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
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50
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Liver Zonation in Health and Disease: Hypoxia and Hypoxia-Inducible Transcription Factors as Concert Masters. Int J Mol Sci 2019; 20:ijms20092347. [PMID: 31083568 PMCID: PMC6540308 DOI: 10.3390/ijms20092347] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Revised: 05/06/2019] [Accepted: 05/08/2019] [Indexed: 02/06/2023] Open
Abstract
The liver and its zonation contribute to whole body homeostasis. Acute and chronic, not always liver, diseases impair proper metabolic zonation. Various underlying pathways, such as β-catenin, hedgehog signaling, and the Hippo pathway, along with the physiologically occurring oxygen gradient, appear to be contributors. Interestingly, hypoxia and hypoxia-inducible transcription factors can orchestrate those pathways. In the current review, we connect novel findings of liver zonation in health and disease and provide a view about the dynamic interplay between these different pathways and cell-types to drive liver zonation and systemic homeostasis.
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