A Negative Feedback of the HIF-1α Pathway via Interferon-Stimulated Gene 15 and ISGylation

Yeh, Yen-Hsiu; Yang, Yuxing; Hsieh, Ming-Shun; Yeh, Yen-Cheng; Li, Tsai-Kun

doi:10.1158/1078-0432.ccr-13-0018

Cited by 36 publications

(49 citation statements)

References 51 publications

(85 reference statements)

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“…Cancer cells treated with TGF-β undergo EMT. We investigated the mechanism underlying TGF-β-induced EMT in A549 (lung), HeLa (cervical), and 769-P (renal) cancer cells, all of which have been established as suitable models for studying EMT in vitro (12)(13)(14)(15). As expected, TGF-β treatment resulted in the acquisition of spindle-fibroblastic morphology, downregulation of epithelial marker E-cadherin, and upregulation of mesenchymal markers fibronectin (FN), vimentin and N-cadherin ( Fig.…”

Section: Resultsmentioning

confidence: 99%

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Rhapontigenin inhibits TGF-β-mediated epithelial-mesenchymal transition via the PI3K/AKT/mTOR pathway and is not associated with HIF-1α degradation

et al. 2016

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The epithelial-mesenchymal transition (EMT) is a pivotal event in cancer cell invasion and metastasis. Emerging evidence suggests that rhapontigenin (Rha) may impede the progression of cancer by disrupting angiogenesis and the EMT. However, the underlying mechanism of Rha has not yet been clarified. In this study, we used transforming growth factor β (TGF-β) to trigger EMT in diverse types of cancer cells and revealed that Rha inhibited TGF-β-induced EMT and derived‑cell invasiveness. The effects of TGF-β were blocked by Rha via interference with the PI3K/AKT/mTOR/GSK3β/β‑catenin signaling pathway. Furthermore, Rha also inhibited TGF-β‑induced expression of transcription regulators Snail and hypoxia-inducible factor 1α (HIF-1α) by causing their degradation by the 26S proteasome. Surprisingly, although HIF-1α was degraded with Snail as a result of Rha exposure, HIF-1α was not a key factor involved in TGF-β-mediated EMT induced by Rha. Knocking-down Snail expression, but not HIF-1α expression, by RNA interference dramatically reversed TGF-β-mediated EMT. Moreover, Rha abolished TGF-β-triggered cell invasiveness. Our results demonstrate that Rha inhibits TGF-β-induced EMT in cancer cells by suppressing the activity of the PI3K/AKT/mTOR pathway. Therefore, Rha may represent a new route for therapeutic intervention in cancer patients and merits future studies to assess its potential.

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Section: Resultsmentioning

confidence: 99%

“…Transient transfections of cancer cell lines were performed using Lipofectamine 2000 (Invitrogen). Whole cell extracts were prepared at specific time-points after transfection and subjected to SDS-PAGE/western blotting or immunoprecipitation assays as described previously (12).…”

Section: Methodsmentioning

confidence: 99%

Rhapontigenin inhibits TGF-β-mediated epithelial-mesenchymal transition via the PI3K/AKT/mTOR pathway and is not associated with HIF-1α degradation

et al. 2016

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“…Indeed, ISG15 is elevated upon traumatic brain injury (Rossi et al, 2015) and after cerebral focal ischemia (Nakka et al, 2011), where it has a neuroprotective effect as shown by increased mortality, exacerbated infarction and worsened neurologic recovery of ISG15-KO mice when they are subjected to transient middle cerebral artery occlusion (Nakka et al, 2011). Interestingly, ISGylation of hypoxia-inducible factor 1α (HIF-1α) disrupts its dimerization and attenuates HIF-1α-mediated gene expression, resulting in decreased tumor growth (Yeh et al, 2013). Furthermore, ISGylation is activated during erythroid differentiation, with a significant decrease in the proportion of fully differentiated erythrocytes and a concomitant increase in the proportion of erythroid precursors in ISG15-KO mice (Maragno et al, 2011).…”

Section: Newly Described Isg15 Functionsmentioning

confidence: 99%

ISGylation – a key to lock the cell gates for preventing the spread of threats

Villarroya-Beltrí

Guerra

2017

Journal of Cell Science

146

120

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Interferon stimulated gene 15 (ISG15) is an ubiquitin-like protein whose expression and conjugation to targets (ISGylation) is induced by infection, interferon (IFN)-α and -β, ischemia, DNA damage and aging. Attention has historically focused on the antiviral effects of ISGylation, which blocks the entry, replication or release of different intracellular pathogens. However, recently, new functions of ISGylation have emerged that implicate it in multiple cellular processes, such as DNA repair, autophagy, protein translation and exosome secretion. In this Review, we discuss the induction and conjugation of ISG15, as well as the functions of ISGylation in the prevention of infections and in cancer progression. We also offer a novel perspective with regard to the latest findings on this pathway, with special attention to the role of ISGylation in the inhibition of exosome secretion, which is mediated by fusion of multivesicular bodies with lysosomes. Finally, we propose that under conditions of stress or infection, ISGylation acts as a defense mechanism to inhibit normal protein translation by modifying protein kinase R (PKR, also known as EIF2AK2), while any newly synthesized proteins are being tagged and thus marked as potentially dangerous. Then, the endosomal system is re-directed towards protein degradation at the lysosome, to effectively 'lock' the cell gates and thus prevent the spread of pathogens, prions and deleterious aggregates through exosomes.

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“…Microarray studies of muscle biopsies from patients with DM have shown overexpression of IFN-I-inducible transcripts, such as interferon-inducible protein 15 (ISG15), Myxovirus resistance A (MxA), Signal Transducer and Activator of Transcription 1 (STAT1) and retinoic acid-inducible gene I (RIG-I), that were validated at the protein level and specifically detected at perifascicular atrophic areas in DM muscle 10 – 14 . Interestingly, it has been shown that ISG15 bears HREs in its promoter and a negative feedback loop for HIF-1α in some cell lines has been proposed 15 . RIG-I is an innate immunity receptor of the retinoic acid-like receptors family and an IFN-stimulated gene itself 16 .…”

Section: Introductionmentioning

confidence: 99%

Hypoxia triggers IFN-I production in muscle: Implications in dermatomyositis

Luna

Suárez‐Calvet

Lleixà

et al. 2017

Sci Rep

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Dermatomyositis is an inflammatory myopathy characterized by symmetrical proximal muscle weakness and skin changes. Muscle biopsy hallmarks include perifascicular atrophy, loss of intramuscular capillaries, perivascular and perimysial inflammation and the overexpression of IFN-inducible genes. Among them, the retinoic-acid inducible gene 1 (RIG-I) is specifically overexpressed in perifascicular areas of dermatomyositis muscle. The aim of this work was to study if RIG-I expression may be modulated by hypoxia using an in vitro approach. We identified putative hypoxia response elements (HRE) in RIG-I regulatory regions and luciferase assays confirmed that RIG-I is a new HIF-inducible gene. We observed an increase expression of RIG-I both by Real time PCR and Western blot in hypoxic conditions in human muscle cells. Cell transfection with a constitutive RIG-I expression vector increased levels of phospho-IRF-3, indicating that RIG-I promotes binding of transcription factors to the enhancer sequence of IFN. Moreover, release of IFN-β was observed in hypoxic conditions. Finally, HIF-1α overexpression was confirmed in the muscle biopsies and in some RIG-I positive perifascicular muscle fibres but not in controls. Our results indicate that hypoxia triggers the production of IFN-I in vitro, and may contribute to the pathogenesis of DM together with other inflammatory factors.

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A Negative Feedback of the HIF-1α Pathway via Interferon-Stimulated Gene 15 and ISGylation

Cited by 36 publications

References 51 publications

Rhapontigenin inhibits TGF-β-mediated epithelial-mesenchymal transition via the PI3K/AKT/mTOR pathway and is not associated with HIF-1α degradation

Rhapontigenin inhibits TGF-β-mediated epithelial-mesenchymal transition via the PI3K/AKT/mTOR pathway and is not associated with HIF-1α degradation

ISGylation – a key to lock the cell gates for preventing the spread of threats

Hypoxia triggers IFN-I production in muscle: Implications in dermatomyositis

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