2. Academic Validation
  3. Citrullination modulation stabilizes HIF-1α to promote tumour progression

Citrullination modulation stabilizes HIF-1α to promote tumour progression

  • Nat Commun. 2024 Sep 3;15(1):7654. doi: 10.1038/s41467-024-51882-w.
Rui Chen # 1,  Zhiyuan Lin # 1,  Shengqi Shen # 2,  Chuxu Zhu 3,  Kai Yan 2,  Caixia Suo 4,  Rui Liu 5,  Haoran Wei 2,  Li Gao 3,  Kaixiang Fan 3,  Huafeng Zhang 5,  Linchong Sun 6,  Ping Gao 7 8
Affiliations

Affiliations

  • 1 School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, China.
  • 2 Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China.
  • 3 School of Medicine, South China University of Technology, Guangzhou, China.
  • 4 Department of Colorectal Surgery, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, China.
  • 5 The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
  • 6 Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China. sunlc@mail.ustc.edu.cn.
  • 7 School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, China. pgao2@ustc.edu.cn.
  • 8 Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China. pgao2@ustc.edu.cn.
  • # Contributed equally.
PMID: 39227578 DOI: 10.1038/s41467-024-51882-w
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.

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