Jmjd6, also known as Jumonji domain-containing 6, is a Fe(II)-and 2-oxoglutarate (2OG)-dependent oxygenase that catalyzes arginine demethylation and lysine hydroxylation of histone and non-histone peptides [3,4,5,8]. It has been implicated in various biological processes such as embryonic development, cellular proliferation, migration, and self-tolerance induction in the thymus [3,4]. It is also involved in pathways like STAT3/IL-10 axis, epigenetic regulation of lipid droplet formation, and heat-shock response [1,2,6].

In tumor-associated macrophages, JMJD6 deficiency attenuated the growth of Lewis lung carcinoma and B16F10 melanomas by reversing M2-like activation of macrophages, and sensitized tumors to immune checkpoint blockades. This indicates that JMJD6 may play a role in tumor progression and immune regulation via the STAT3/IL-10 signaling [1]. In clear cell renal cell carcinoma, downregulation of JMJD6 abolished colony formation in vitro and inhibited orthotopic tumor growth in vivo, suggesting its importance in tumor development through the JMJD6-DGAT1 axis [2]. In embryonic stem (ES) cells, depletion of Jmjd6 led to downregulation of pluripotency genes, apoptosis, and reduced BrdU incorporation, while its overexpression enhanced reprogramming efficiency of mouse embryonic fibroblasts (MEFs), showing its role in ES cell homeostasis and somatic cell reprogramming [7].

In conclusion, Jmjd6 is crucial for multiple biological functions including tumor development, macrophage polarization, and ES cell homeostasis. Studies using gene-knockout or conditional-knockout models have revealed its significance in these processes, especially in tumor-related diseases, highlighting its potential as a therapeutic target [1,2,7].

References:

1. Chen, Siyuan, Wang, Manni, Lu, Tianqi, Wei, Yuquan, Wei, Xiawei. 2023. JMJD6 in tumor-associated macrophage regulates macrophage polarization and cancer progression via STAT3/IL-10 axis. In Oncogene, 42, 2737-2750. doi:10.1038/s41388-023-02781-9. https://pubmed.ncbi.nlm.nih.gov/37567973/

2. Zhou, Jin, Simon, Jeremy M, Liao, Chengheng, Brugarolas, James, Zhang, Qing. 2022. An oncogenic JMJD6-DGAT1 axis tunes the epigenetic regulation of lipid droplet formation in clear cell renal cell carcinoma. In Molecular cell, 82, 3030-3044.e8. doi:10.1016/j.molcel.2022.06.003. https://pubmed.ncbi.nlm.nih.gov/35764091/

3. Shen, Xiaoli, De Geyter, Christian, Zhang, Hong, Huang, Guoning. 2022. Regulatory role of JMJD6 in placental development. In Expert reviews in molecular medicine, 24, e34. doi:10.1017/erm.2022.30. https://pubmed.ncbi.nlm.nih.gov/36222080/

4. Kwok, Janice, O'Shea, Marie, Hume, David A, Lengeling, Andreas. 2017. Jmjd6, a JmjC Dioxygenase with Many Interaction Partners and Pleiotropic Functions. In Frontiers in genetics, 8, 32. doi:10.3389/fgene.2017.00032. https://pubmed.ncbi.nlm.nih.gov/28360925/

5. Vangimalla, Shiva Shankar, Ganesan, Murali, Kharbanda, Kusum K, Osna, Natalia A. 2017. Bifunctional Enzyme JMJD6 Contributes to Multiple Disease Pathogenesis: New Twist on the Old Story. In Biomolecules, 7, . doi:10.3390/biom7020041. https://pubmed.ncbi.nlm.nih.gov/28587176/

6. Alasady, Milad J, Koeva, Martina, Takagishi, Seesha R, Taipale, Mikko, Mendillo, Marc L. 2024. An HSF1-JMJD6-HSP feedback circuit promotes cell adaptation to proteotoxic stress. In Proceedings of the National Academy of Sciences of the United States of America, 121, e2313370121. doi:10.1073/pnas.2313370121. https://pubmed.ncbi.nlm.nih.gov/38985769/

7. Ji, Guanxu, Xiao, Xiaoxiao, Huang, Min, Wu, Qiang. 2022. Jmjd6 regulates ES cell homeostasis and enhances reprogramming efficiency. In Heliyon, 8, e09105. doi:10.1016/j.heliyon.2022.e09105. https://pubmed.ncbi.nlm.nih.gov/35846449/

8. Böttger, Angelika, Islam, Md Saiful, Chowdhury, Rasheduzzaman, Schofield, Christopher J, Wolf, Alexander. . The oxygenase Jmjd6--a case study in conflicting assignments. In The Biochemical journal, 468, 191-202. doi:10.1042/BJ20150278. https://pubmed.ncbi.nlm.nih.gov/25997831/