Non-Canonical Mechanisms Regulating Hypoxia-Inducible Factor 1 Alpha in Cancer

Iommarini, Luisa; Porcelli, Anna Maria; Gasparre, Giuseppe; Kurelac, Ivana

doi:10.3389/fonc.2017.00286

Cited by 175 publications

(142 citation statements)

References 101 publications

(113 reference statements)

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“…Hypoxia is common in some regions of tumor tissue due to lack of vascularity (215). HIF-1α is usually upregulated upon hypoxia, and is positively correlated with the malignancy of certain tumors (216). Previous studies have identified HIF-1α as a negative regulator of iTreg cell differentiation, while it promotes Th17 cell differentiation (78, 217).…”

Section: Tumor Tissuementioning

confidence: 99%

Metabolic Control of Treg Cell Stability, Plasticity, and Tissue-Specific Heterogeneity

2019

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Regulatory T (Treg) cells are crucial for peripheral immune tolerance and prevention of autoimmunity and tissue damage. Treg cells are inherently defined by the expression of the transcription factor Foxp3, which enforces lineage development and immune suppressive function of these cells. Under various conditions as observed in autoimmunity, cancer and non-lymphoid tissues, a proportion of Treg cells respond to specific environmental signals and display altered stability, plasticity and tissue-specific heterogeneity, which further shape their context-dependent suppressive functions. Recent studies have revealed that metabolic programs play pivotal roles in controlling these processes in Treg cells, thereby considerably expanding our understanding of Treg cell biology. Here we summarize these recent advances that highlight how cell-extrinsic factors, such as nutrients, vitamins and metabolites, and cell-intrinsic metabolic programs, orchestrate Treg cell stability, plasticity, and tissue-specific heterogeneity. Understanding metabolic regulation of Treg cells should provide new insight into immune homeostasis and disease, with important therapeutic implications for autoimmunity, cancer, and other immune-mediated disorders.

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Section: Tumor Tissuementioning

confidence: 99%

Metabolic Control of Treg Cell Stability, Plasticity, and Tissue-Specific Heterogeneity

2019

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“…Succinate can be transported from mitochondria to the cytosol, where it inhibits PHD via product inhibition . Just as succinate stabilizes HIF, also other metabolites, such as fumarate, pyruvate, and lactate, can inhibit PHD resulting in HIF stabilization . The upregulation of glycolysis by HIF1α and subsequent activation of HIF1α by glycolytic enzymes and TCA intermediates creates a positive feedback loop that drives macrophages to produce IL1β and ROS resulting in eradication of the invading pathogens .…”

Section: Crosstalk Between Hif and Sepsismentioning

confidence: 99%

Hypoxia‐inducible factors in metabolic reprogramming during sepsis

2020

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Sepsis is a highly heterogeneous syndrome that is caused by an imbalanced host response to infection. Despite huge investments, sepsis remains a contemporary threat with significant burden on health systems. Vascular dysfunction and elevated oxygen consumption by highly metabolically active immune cells result in tissue hypoxia during inflammation. The transcription factor hypoxia-inducible factor-1a (HIF1a), and its family members, plays an important role in cellular metabolism and adaptation to cellular stress caused by hypoxia. In this review, we discuss the role of HIF in sepsis. We show possible mechanisms by which the inflammatory response activated during sepsis affects the HIF pathway. The activated HIF pathway in turn changes the metabolism of both innate and adaptive immune cells. As HIF expression in leukocytes of septic patients can be directly linked with mortality, we discuss multiple ways of interfering with the HIF signaling pathway.

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“…Fourth, the rat IR model used in the present study did not fully reflect the actual clinical situations. Additionally, changes in ambient oxygen concentrations and variations of oxygen diffusion in tissues have a strong impact on HIF-1α stabilization when working in vivo because of the ultrashort half-life (< 5 min) of HIF-1α in oxygenated atmosphere [37]. These unstable natures of HIF-1α became big obstacles in the present study to examine the expression of HIF-1α in blood samples and heart tissues of rats.…”

Section: Discussionmentioning

confidence: 95%

Investigating the potential effects of selective histone deacetylase 6 inhibitor ACY1215 on infarct size in rats with cardiac ischemia-reperfusion injury

Lin

Hsu

HuangFu

et al. 2020

BMC Pharmacol Toxicol

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Background: Despite the fact that histone deacetylase (HDAC) inhibitors have been tested to treat various cardiovascular diseases, the effects of selective HDAC6 inhibitor ACY1215 on infarct size during cardiac ischemiareperfusion (IR) injury still remain unknown. In the present study we aimed to investigate the effects of ACY1215 on infarct size in rats with cardiac IR injury, as well as to examine the association between HDAC6 inhibitors and the gene expression of hypoxia inducible factor-1α (HIF-1α), a key regulator of cellular responses to hypoxia. Methods: By using computational analysis of high-throughput expression profiling dataset, the association between HDAC inhibitors (pan-HDAC inhibitors panobinostat and vorinostat, and HDAC6 inhibitor ISOX) and their effects on HIF-1α geneexpression were evaluated. The male Wistar rats treated with ligation of left coronary artery followed by reperfusion were used as a cardiac IR model. ACY1215 (50 mg/kg), pan-HDAC inhibitor MPT0E028 (25 mg/kg), and vehicle were intraperitoneally injected within 5 min before reperfusion. The infarct size in rat myocardium was determined by 2,3,5-triphenyltetrazolium chloride staining. The serum levels of transforming growth factor-β (TGF-β) and C-reactive protein (CRP) were also determined. Results: The high-throughput gene expression assay showed that treatment of ISOX was associated with a more decreased gene expression of HIF-1α than that of panobinostat and vorinostat. Compared to control rats, ACY1215treated rats had a smaller infarct size (49.75 ± 9.36% vs. 19.22 ± 1.70%, p < 0.05), while MPT0E028-treated rats had a similar infarct size to control rats. ACY-1215-and MPT0E028-treated rats had a trend in decreased serum TGF-β levels, but not statistically significant. ACY1215-treated rats also had higher serum CRP levels compared to control rats (641.6 μg/mL vs. 961.37 ± 64.94 μg/mL, p < 0.05). Conclusions: Our research indicated that HDAC6 inhibition by ACY1215 might reduce infarct size in rats with cardiac IR injury possibly through modulating HIF-1α expression. TGF-β and CRP should be useful biomarkers to monitor the use of ACY1215 in cardiac IR injury.

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Non-Canonical Mechanisms Regulating Hypoxia-Inducible Factor 1 Alpha in Cancer

Cited by 175 publications

References 101 publications

Metabolic Control of Treg Cell Stability, Plasticity, and Tissue-Specific Heterogeneity

Metabolic Control of Treg Cell Stability, Plasticity, and Tissue-Specific Heterogeneity

Hypoxia‐inducible factors in metabolic reprogramming during sepsis

Investigating the potential effects of selective histone deacetylase 6 inhibitor ACY1215 on infarct size in rats with cardiac ischemia-reperfusion injury

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