NCHU Professor Hui-Chih Hung’s Team Published in PNAS: PAD4 Enzyme Silences the Cancer Guardian p53
2025-11-21
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A research team led by Professor Hui-Chih Hung at National Chung Hsing University (NCHU) has made a breakthrough discovery revealing how the enzyme PAD4 “switches off” the tumor suppressor protein p53, known as the guardian of the genome. The study, titled “Citrullination negatively regulates the functions of the p53 protein and opposes its ubiquitination and degradation,” was published in the prestigious journal Proceedings of the National Academy of Sciences (PNAS) on October 14, 2025.
The team found that PAD4 catalyzes a post-translational modification known as citrullination, which removes positive charges from key arginine residues on p53 (R158, R282, R283). This alteration distorts p53’s structure, preventing it from forming tetramers or binding DNA, thereby silencing its tumor-suppressive activity.
Moreover, PAD4-mediated citrullination disrupts the interaction between p53 and its E3 ubiquitin ligase MDM2, leading to an accumulation of inactive p53. Treatment with PAD4 inhibitors such as GSK484 and BB-Cl-amidine was shown to block this modification and restore part of p53’s function, highlighting PAD4 as a promising therapeutic target for cancer therapy.
Professor Hung explained, “PAD4 acts like a mute button on p53. If we can block PAD4, we may be able to turn its power back on and let it fight cancer again.”
This study provides the first molecular evidence that PAD4 directly modifies and suppresses p53, explaining how cancer cells can inactivate p53 without mutations. It opens new opportunities for PAD4-targeted drug development to reactivate natural tumor defense mechanisms.
The research was led by Dr. Yi-Fang Yang (first author) and Professor Hui-Chih Hung (corresponding author), in collaboration with the Technical University of Munich. The work was supported by the National Science and Technology Council (NSTC), and the Ministry of Education’s Higher Education Sprout Project.
https://www.pnas.org/doi/10.1073/pnas.2423526122
The team found that PAD4 catalyzes a post-translational modification known as citrullination, which removes positive charges from key arginine residues on p53 (R158, R282, R283). This alteration distorts p53’s structure, preventing it from forming tetramers or binding DNA, thereby silencing its tumor-suppressive activity.
Moreover, PAD4-mediated citrullination disrupts the interaction between p53 and its E3 ubiquitin ligase MDM2, leading to an accumulation of inactive p53. Treatment with PAD4 inhibitors such as GSK484 and BB-Cl-amidine was shown to block this modification and restore part of p53’s function, highlighting PAD4 as a promising therapeutic target for cancer therapy.
Professor Hung explained, “PAD4 acts like a mute button on p53. If we can block PAD4, we may be able to turn its power back on and let it fight cancer again.”
This study provides the first molecular evidence that PAD4 directly modifies and suppresses p53, explaining how cancer cells can inactivate p53 without mutations. It opens new opportunities for PAD4-targeted drug development to reactivate natural tumor defense mechanisms.
The research was led by Dr. Yi-Fang Yang (first author) and Professor Hui-Chih Hung (corresponding author), in collaboration with the Technical University of Munich. The work was supported by the National Science and Technology Council (NSTC), and the Ministry of Education’s Higher Education Sprout Project.
https://www.pnas.org/doi/10.1073/pnas.2423526122
NCHU Professor Hui-Chih Hung’s Team Published in PNAS: PAD4 Enzyme Silences the Cancer Guardian p53
NCHU Professor Hui-Chih Hung’s Team Published in PNAS: PAD4 Enzyme Silences the Cancer Guardian p53
