The EGLN-HIF O 2 -Sensing System: Multiple Inputs and Feedbacks

Ivan, Mircea; Kaelin, William G.

doi:10.1016/j.molcel.2017.06.002

Cited by 220 publications

(172 citation statements)

References 76 publications

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“…Therefore, HIF is a primary regulator of the adaptive transcriptional response to hypoxia. Notably, HIF is self-regulated by several negative feedback loops in tissues; these include the upregulation of the HIF hydroxylases PHD2 and PHD3, and microRNAs, which control HIF expression levels 46 . Furthermore, not all transcriptional responses to hypoxia are under the control of the HIF pathway, and a range of other transcription factors also display hypoxic sensitivity and can influence the impact of microenvironmental hypoxia on immune cell function 22 .…”

Section: Transcriptional Responses To Hypoxiamentioning

confidence: 99%

Regulation of immunity and inflammation by hypoxia in immunological niches

2017

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Immunological niches are focal sites of immune activity that can have varying microenvironmental features. Hypoxia is a feature of physiological and pathological immunological niches. The impact of hypoxia on immunity and inflammation can vary depending on the microenvironment and immune processes occurring in a given niche. In physiological immunological niches, such as the bone marrow, lymphoid tissue, placenta and intestinal mucosa, physiological hypoxia controls innate and adaptive immunity by modulating immune cell proliferation, development and effector function, largely via transcriptional changes driven by hypoxia-inducible factor (HIF). By contrast, in pathological immunological niches, such as tumours and chronically inflamed, infected or ischaemic tissues, pathological hypoxia can drive tissue dysfunction and disease development through immune cell dysregulation. Here, we differentiate between the effects of physiological and pathological hypoxia on immune cells and the consequences for immunity and inflammation in different immunological niches. Furthermore, we discuss the possibility of targeting hypoxia-sensitive pathways in immune cells for the treatment of inflammatory disease.

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Section: Transcriptional Responses To Hypoxiamentioning

confidence: 99%

Regulation of immunity and inflammation by hypoxia in immunological niches

2017

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“…EGLN1 is a prolyl hydroxylase, and several PHD inhibitors have been described (41,42), which prevent the degradation of HIF1A. Specifically, compound FG-4592, also known as Roxadustat, is currently being evaluated for the treatment of anemia in dialysisdependent chronic kidney disease (CKD) and nondialysisdependent CKD (42)(43)(44)(45).…”

Section: Pharmacologic Inhibition Of Egln1 or Vhl Inhibits Proliferatmentioning

confidence: 99%

Genome-Wide Interrogation of Human Cancers Identifies EGLN1 Dependency in Clear Cell Ovarian Cancers

Price

Gill

et al. 2019

Cancer Research

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We hypothesized that candidate dependencies for which there are small molecules that are either approved or in advanced development for a nononcology indication may represent potential therapeutic targets. To test this hypothesis, we performed genome-scale loss-of-function screens in hundreds of cancer cell lines. We found that knockout of EGLN1, which encodes prolyl hydroxylase domain-containing protein 2 (PHD2), reduced the proliferation of a subset of clear cell ovarian cancer cell lines in vitro. EGLN1-dependent cells exhibited sensitivity to the pan-EGLN inhibitor FG-4592. The response to FG-4592 was reversed by deletion of HIF1A, demonstrating that EGLN1 dependency was related to negative regulation of HIF1A. We also found that ovarian clear cell tumors susceptible to both genetic and pharmacologic inhibition of EGLN1 required intact HIF1A. Collectively, these observations identify EGLN1 as a cancer target with therapeutic potential.Significance: These findings reveal a differential dependency of clear cell ovarian cancers on EGLN1, thus identifying EGLN1 as a potential therapeutic target in clear cell ovarian cancer patients.

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“…Under normoxic conditions, PHD2 uses O 2 and α‐ketoglutarate to hydroxylate the HIF‐α subunit, which is then recognized by the von Hippel–Lindau tumor suppressor protein (pVHL) and subjected to proteasomal degradation. Under hypoxic conditions, PHD2 is inactive, and HIF transcriptionally activates hypoxia‐related genes, including vascular endothelial growth factor and erythropoietin …”

Section: From Metabolic Dysfunction To Therapeuticsmentioning

confidence: 99%

“…Under hypoxic conditions, PHD2 is inactive, and HIF transcriptionally activates hypoxia-related genes, including vascular endothelial growth factor and erythropoietin. 32,33 Activating HIF function can be advantageous in diseases like anemia-PHD2 inhibitors are being investigated in phase 3 clinical trials for the treatment of chronic kidney disease-associated anemia, 34 and the first inhibitor, roxadustat, was approved for this indication in China in 2018. 35 However, increased HIF activity due to mutations that inactivate pVHL is a common feature of RCC.…”

Section: From Metabolic Dysfunction To Therapeuticsmentioning

confidence: 99%

Leveraging insights into cancer metabolism—a symposium report

Cable¹,

Finley

et al. 2019

Annals of the New York Academy of Sciences

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Tumor cells have devised unique metabolic strategies to garner enough nutrients to sustain continuous growth and cell division. Oncogenic mutations may alter metabolic pathways to unlock new sources of energy, and cells take the advantage of various scavenging pathways to ingest material from their environment. These changes in metabolism result in a metabolic profile that, in addition to providing the building blocks for macromolecules, can also influence cell signaling pathways to promote tumor initiation and progression. Understanding what pathways tumor cells use to synthesize the materials necessary to support metabolic growth can pave the way for new cancer therapeutics. Potential strategies include depriving tumors of the materials needed to grow or targeting pathways involved in dependencies that arise by virtue of their altered metabolis.

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The EGLN-HIF O 2 -Sensing System: Multiple Inputs and Feedbacks

Cited by 220 publications

References 76 publications

Regulation of immunity and inflammation by hypoxia in immunological niches

Regulation of immunity and inflammation by hypoxia in immunological niches

Genome-Wide Interrogation of Human Cancers Identifies EGLN1 Dependency in Clear Cell Ovarian Cancers

Leveraging insights into cancer metabolism—a symposium report

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