Citrullination modulation stabilizes HIF-1α to promote tumour progression

Rui Chen, Zhiyuan Lin, Shengqi Shen, Chuxu Zhu, Kai Yan, Caixia Suo, Rui Liu, Haoran Wei, Li Gao, Kaixiang Fan, Huafeng Zhang, Linchong Sun () and Ping Gao ()
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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

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51882-w

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