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- Title
Citrullination modulation stabilizes HIF-1α to promote tumour progression.
- Authors
Chen, Rui; Lin, Zhiyuan; Shen, Shengqi; Zhu, Chuxu; Yan, Kai; Suo, Caixia; Liu, Rui; Wei, Haoran; Gao, Li; Fan, Kaixiang; Zhang, Huafeng; Sun, Linchong; Gao, Ping
- 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. Post-translational modifications on HIF-1α can regulate its stability and activity in tumoral processes. Here, the authors show that PADI4-mediated citrullination avoids HIF-1α degradation to promote hepatocellular carcinoma progression and this can be prevented by a PADI4 antagonist
- Subjects
ARGININE deiminase; POST-translational modification; HYPOXIA-inducible factors; HEPATOCELLULAR carcinoma; UBIQUITINATION
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-51882-w