Citrullination modulation stabilizes HIF-1α to promote tumour progression.

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Citrullination is a posttranslational modification involved in physiological and pathological processes.
• The role of citrullination in tumor progression and its therapeutic potential remain underexplored.

Purpose of the Study:

• To investigate the role of citrullination in tumor progression.
• To explore the therapeutic significance of targeting citrullination pathways in cancer.

Main Methods:

• Investigated the interaction between peptidyl arginine deiminase 4 (PADI4) and hypoxia-inducible factor 1α (HIF-1α).
• Analyzed the effect of PADI4-mediated citrullination on HIF-1α stability and degradation.
• Examined the expression of citrullinated HIF-1α, HIF-1α, and PADI4 in hepatocellular carcinoma (HCC) tissues.
• Tested the efficacy of dihydroergotamine mesylate (DHE) as a PADI4 antagonist in preclinical models.

Main Results:

• PADI4 directly interacts with and citrullinates HIF-1α at R698, promoting HIF-1α stabilization.
• PADI4-mediated citrullination of HIF-1α at R698 inhibits von Hippel-Lindau (VHL) binding, preventing ubiquitination and proteasome degradation.
• High expression of citrullinated HIF-1α, HIF-1α, and PADI4 was observed in HCC tissues.
• Dihydroergotamine mesylate (DHE) antagonizes PADI4 activity and suppresses tumor progression.

Conclusions:

• Citrullination is a novel posttranslational modification regulating HIF-1α stability.
• PADI4-mediated HIF-1α citrullination contributes to cancer development.
• Targeting PADI4-mediated HIF-1α citrullination presents a promising therapeutic strategy for cancers with aberrant HIF-1α expression.