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Citrullination modulation stabilizes HIF-1α to promote tumour progression

Author

Listed:
  • Rui Chen

    (South China University of Technology, Guangzhou International Campus)

  • Zhiyuan Lin

    (South China University of Technology, Guangzhou International Campus)

  • Shengqi Shen

    (Southern Medical University)

  • Chuxu Zhu

    (South China University of Technology)

  • Kai Yan

    (Southern Medical University)

  • Caixia Suo

    (South China University of Technology)

  • Rui Liu

    (University of Science and Technology of China)

  • Haoran Wei

    (Southern Medical University)

  • Li Gao

    (South China University of Technology)

  • Kaixiang Fan

    (South China University of Technology)

  • Huafeng Zhang

    (University of Science and Technology of China)

  • Linchong Sun

    (Southern Medical University)

  • Ping Gao

    (South China University of Technology, Guangzhou International Campus
    Southern Medical University)

Abstract

Citrullination plays an essential role in various physiological or pathological processes, however, whether citrullination is involved in regulating tumour progression and the potential therapeutic significance have not been well explored. Here, we find that peptidyl arginine deiminase 4 (PADI4) directly interacts with and citrullinates hypoxia-inducible factor 1α (HIF-1α) at R698, promoting HIF-1α stabilization. Mechanistically, PADI4-mediated HIF-1αR698 citrullination blocks von Hippel-Lindau (VHL) binding, thereby antagonizing HIF-1α ubiquitination and subsequent proteasome degradation. We also show that citrullinated HIF-1αR698, HIF-1α and PADI4 are highly expressed in hepatocellular carcinoma (HCC) tumour tissues, suggesting a potential correlation between PADI4-mediated HIF-1αR698 citrullination and cancer development. Furthermore, we identify that dihydroergotamine mesylate (DHE) acts as an antagonist of PADI4, which ultimately suppresses tumour progression. Collectively, our results reveal citrullination as a posttranslational modification related to HIF-1α stability, and suggest that targeting PADI4-mediated HIF-1α citrullination is a promising therapeutic strategy for cancers with aberrant HIF-1α expression.

Suggested Citation

  • Rui Chen & Zhiyuan Lin & Shengqi Shen & Chuxu Zhu & Kai Yan & Caixia Suo & Rui Liu & Haoran Wei & Li Gao & Kaixiang Fan & Huafeng Zhang & Linchong Sun & Ping Gao, 2024. "Citrullination modulation stabilizes HIF-1α to promote tumour progression," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51882-w
    DOI: 10.1038/s41467-024-51882-w
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    References listed on IDEAS

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    1. A. E. Yuzhalin & A. N. Gordon-Weeks & M. L. Tognoli & K. Jones & B. Markelc & R. Konietzny & R. Fischer & A. Muth & E. O’Neill & P. R. Thompson & P. J. Venables & B. M. Kessler & S. Y. Lim & R. J. Mus, 2018. "Colorectal cancer liver metastatic growth depends on PAD4-driven citrullination of the extracellular matrix," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    2. Maria A. Christophorou & Gonçalo Castelo-Branco & Richard P. Halley-Stott & Clara Slade Oliveira & Remco Loos & Aliaksandra Radzisheuskaya & Kerri A. Mowen & Paul Bertone & José C. R. Silva & Magdalen, 2014. "Citrullination regulates pluripotency and histone H1 binding to chromatin," Nature, Nature, vol. 507(7490), pages 104-108, March.
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