A negative feedback of the HIF-1α pathway via interferon-stimulated gene 15 and ISGylation

Yen-Hsiu Yeh, Yu-Chen Yang, Mei-Yi Hsieh, Yen-Cheng Yeh, Tsai-Kun Li

Research output: Contribution to journalArticlepeer-review

31 Citations (Scopus)


Purpose: The IFN-stimulated gene 15 (ISG15)- and ubiquitin-conjugation pathways play roles in mediating hypoxic and inflammatory responses. To identify interaction(s) between these two tumor microenvironments, we investigated the effect of ISG15 on the activity of the master hypoxic transcription factor HIF-1α. Experimental Design: IFN and desferoxamine treatments were used to induce the expression of ISGs and HIF-1α, respectively. Interactions between HIF-1α and the ISG15 and ISGylation system were studied using knockdown of mRNA expression, immunoblotting, coimmunoprecipitation, and pull-down analyses. Effects of the ISG15 and ISGylation system on the HIF-1α-directed processes were examined using reporter, reverse transcription polymerase chain reaction (RT-PCR), and tumorigenic growth assays. Results: We found that the level of the free form of HIF-1α is differentially regulated by IFN treatment, and that the free ISG15 level is lower under hypoxia. Mechanism-directed studies have shown that HIF-1α not only interacts physically with ISG15, but is also ISGylated in multiple domains. ISG15 expression disrupts the functional dimerization of HIF-1α and -1β. Subsequently, expression of the ISG15 and/or ISGylation system attenuates HIF-1α-mediated gene expression and tumorigenic growth. Conclusion: In summary, our results revealed cross-talk between inflammatory and hypoxic pathways through the ISGylation of HIF-1α. On the basis of these results, we propose a novel negative feedback loop for the HIF-1α-mediated pathway involving the regulation of HIF-1α via IFN-induced ISGylation. © 2013 American Association for Cancer Research.
Original languageEnglish
Pages (from-to)5927-5939
Number of pages13
JournalClinical Cancer Research
Issue number21
Publication statusPublished - 2013
Externally publishedYes


  • deferoxamine
  • hypoxia inducible factor 1alpha
  • hypoxia inducible factor 1beta
  • interferon
  • interferon stimulated gene 15 protein
  • messenger RNA
  • ubiquitin
  • unclassified drug
  • animal experiment
  • animal model
  • article
  • cell hypoxia
  • cell proliferation
  • controlled study
  • dimerization
  • gene expression
  • human
  • human cell
  • immunoblotting
  • immunoprecipitation
  • inflammation
  • ISGylation
  • mouse
  • negative feedback
  • nonhuman
  • priority journal
  • protein domain
  • protein processing
  • protein protein interaction
  • reverse transcription polymerase chain reaction
  • tumor growth
  • tumor xenograft
  • Anoxia
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Transformation, Neoplastic
  • Cytokines
  • Gene Expression Regulation
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Interferons
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Response Elements
  • Signal Transduction
  • Ubiquitins


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