Padi4, also known as peptidyl arginine deiminase type 4 or PAD4, is a Ca2+-dependent posttranslational modification enzyme. It catalyzes the conversion of arginine residues to non-coded citrulline residues. Padi4-mediated citrullination is associated with transcriptional regulation, and its dysregulation is involved in multiple diseases. It may be related to pathways such as epithelial-mesenchymal transition (EMT), apoptosis, and neutrophil extracellular traps (NETs) formation, which are crucial in various biological processes and disease developments [8].

In cancer research, a rare African-specific germline variant of TP53 (Y107H) revealed Padi4 as a key tumor-suppressive p53 target gene. Y107H mice, which have impaired Padi4 transactivation, develop spontaneous cancers and metastases, indicating Padi4's role in tumor suppression [1]. In lung cancer, knockdown of Padi4 attenuates cell invasion and migration by affecting the EMT-associated Snail1/Smad3/4 transcriptional complex [3]. In gastric cancer, Padi4 promotes EMT and metastasis via up-regulation of interleukin 8 [4]. In osteosarcoma, Padi4 promotes cell invasion and migration by promoting EMT, while its inhibitor suppresses these effects [6]. In a mouse lung carcinogenetic model, berberine, which can inhibit Padi4 expression, reduces the number of lung tumor nodules [5].

In conclusion, Padi4 plays significant roles in cancer development and metastasis, mainly through its influence on EMT-related processes. Studies using mouse models, like those with the Y107H variant of TP53, have been crucial in uncovering Padi4's tumor-suppressive function. Additionally, its association with rheumatoid arthritis, as shown by polymorphism and haplotype studies in Egyptian patients [2] and meta-analysis in Asian and Caucasian populations [7], further emphasizes its importance in disease-related research.

References:

1. Indeglia, Alexandra, Leung, Jessica C, Miller, Sven A, Karanicolas, John, Murphy, Maureen E. . An African-Specific Variant of TP53 Reveals PADI4 as a Regulator of p53-Mediated Tumor Suppression. In Cancer discovery, 13, 1696-1719. doi:10.1158/2159-8290.CD-22-1315. https://pubmed.ncbi.nlm.nih.gov/37140445/

2. Abd-Allah, Somia H, el-Shal, Amal S, Shalaby, Sally M, el-Najjar, Amany R, el-Shahawy, Eman E. 2011. PADI4 polymorphisms and related haplotype in rheumatoid arthritis patients. In Joint bone spine, 79, 124-8. doi:10.1016/j.jbspin.2011.07.006. https://pubmed.ncbi.nlm.nih.gov/21981985/

3. Liu, Meiyan, Qu, Yang, Teng, Xue, Li, Chunhong, Cai, Li. 2019. PADI4‑mediated epithelial‑mesenchymal transition in lung cancer cells. In Molecular medicine reports, 19, 3087-3094. doi:10.3892/mmr.2019.9968. https://pubmed.ncbi.nlm.nih.gov/30816464/

4. Chang, Xiao-Tian, Wu, Hui, Li, Hui-Lin, Li, Hong-Lei, Zheng, Ya-Bing. 2022. PADI4 promotes epithelial-mesenchymal transition(EMT) in gastric cancer via the upregulation of interleukin 8. In BMC gastroenterology, 22, 25. doi:10.1186/s12876-022-02097-0. https://pubmed.ncbi.nlm.nih.gov/35045833/

5. Gu, Wenwen, Zhang, Mengdi, Gao, Fan, Guo, Zhenzhen, Du, Gangjun. 2022. Berberine regulates PADI4-related macrophage function to prevent lung cancer. In International immunopharmacology, 110, 108965. doi:10.1016/j.intimp.2022.108965. https://pubmed.ncbi.nlm.nih.gov/35764017/

6. Zhai, Qiaoli, Qin, Jie, Jin, Xiaodong, Li, Tao, Xiang, Xinxin. 2020. PADI4 modulates the invasion and migration of osteosarcoma cells by down-regulation of epithelial-mesenchymal transition. In Life sciences, 256, 117968. doi:10.1016/j.lfs.2020.117968. https://pubmed.ncbi.nlm.nih.gov/32544462/

7. Lu, Chao, Xu, Ke, Guo, Hao, Hao, Yang Quan, Xu, Peng. 2018. The relationship of PADI4_94 polymorphisms with the morbidity of rheumatoid arthritis in Caucasian and Asian populations: a meta-analysis and system review. In Clinical rheumatology, 37, 289-296. doi:10.1007/s10067-017-3964-3. https://pubmed.ncbi.nlm.nih.gov/29302826/

8. Wu, Xiangmei, Wang, Yuji, Wang, Wenjing. . The Role of Peptidyl Arginine Deiminase IV(PADI4) in Cancers. In Anti-cancer agents in medicinal chemistry, 23, 256-265. doi:10.2174/1871520622666220614115309. https://pubmed.ncbi.nlm.nih.gov/35702765/