Sephs2, or selenophosphate synthetase 2, is an enzyme in the selenocysteine biosynthesis pathway. It synthesizes selenophosphate from selenide and ATP, providing the essential selenium donor for the biosynthesis of selenocysteine-tRNA, which is crucial for incorporating selenocysteine into selenoproteins like glutathione peroxidases and thioredoxin reductases. This process is vital for cellular function, especially in maintaining redox homeostasis [2,3,5]. Genetic models such as gene knockout mouse models can be valuable in studying its functions.

In cancer cells, Sephs2 is essential for survival as it detoxifies selenide, an intermediate in selenocysteine biosynthesis. Breast and other cancer cells take up selenium due to the secondary function of SLC7A11, which promotes selenocysteine biosynthesis and protects against ferroptosis. However, the produced selenide is poisonous and requires Sephs2 for processing. Loss of Sephs2 impairs the growth of orthotopic mammary-tumour xenografts in mice, highlighting its significance in cancer growth [1]. In acute myeloid leukemia (AML), a MYB-regulated enhancer upregulates Sephs2, promoting selenoprotein production and antioxidant function needed for AML survival. Sephs2 knockout significantly delays leukemogenesis in vivo with little effect on normal hematopoiesis [4].

In conclusion, Sephs2 plays a crucial role in selenocysteine metabolism and redox-related cellular functions. Through gene knockout studies in mouse models, its importance in cancer, particularly in breast cancer and AML, has been revealed. These findings suggest Sephs2 could be a potential therapeutic target in these disease areas.

References:

1. Carlisle, Anne E, Lee, Namgyu, Matthew-Onabanjo, Asia N, Shaw, Leslie M, Kim, Dohoon. 2020. Selenium detoxification is required for cancer-cell survival. In Nature metabolism, 2, 603-611. doi:10.1038/s42255-020-0224-7. https://pubmed.ncbi.nlm.nih.gov/32694795/

2. Nunziata, Carmine, Polo, Andrea, Sorice, Angela, Budillon, Alfredo, Costantini, Susan. 2019. Structural analysis of human SEPHS2 protein, a selenocysteine machinery component, over-expressed in triple negative breast cancer. In Scientific reports, 9, 16131. doi:10.1038/s41598-019-52718-0. https://pubmed.ncbi.nlm.nih.gov/31695102/

3. Na, Jiwoon, Jung, Jisu, Bang, Jeyoung, Hatfield, Dolph L, Lee, Byeong Jae. 2018. Selenophosphate synthetase 1 and its role in redox homeostasis, defense and proliferation. In Free radical biology & medicine, 127, 190-197. doi:10.1016/j.freeradbiomed.2018.04.577. https://pubmed.ncbi.nlm.nih.gov/29715549/

4. Eagle, Kenneth, Jiang, Yajian, Shi, Xiangguo, Lin, Charles Y, Nakada, Daisuke. 2022. An oncogenic enhancer encodes selective selenium dependency in AML. In Cell stem cell, 29, 386-399.e7. doi:10.1016/j.stem.2022.01.003. https://pubmed.ncbi.nlm.nih.gov/35108519/

5. Gladyshev, Vadim N, Arnér, Elias S, Berry, Marla J, Whanger, Philip D, Zhang, Yan. 2016. Selenoprotein Gene Nomenclature. In The Journal of biological chemistry, 291, 24036-24040. doi:. https://pubmed.ncbi.nlm.nih.gov/27645994/