St8sia4, also known as ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 4, is an enzyme involved in sialylation, specifically in the synthesis of polysialic acid (PSA) [3,7]. Sialylation is a glycosylation pattern associated with various biological processes and disease states. The ST8SIA4-dependent polysialylation is part of a developmental program required for germ layer formation from human pluripotent stem cells [3].

In breast cancer, BRCA1 deficiency increases VEGFA and IL6 expression to activate TGFβ-ST8SIA4 signaling. High levels of ST8SIA4 lead to PSA accumulation on mammary epithelial membranes, promoting metastasis and immunotherapy resistance [1]. In cholangiocarcinoma, miR-144-5p and miR-451a inhibit cell growth by decreasing ST8SIA4 expression [4]. Also, in breast cancer, miR-26a/26b targets ST8SIA4, and knocking down ST8SIA4 inhibits malignant behaviors [5]. In chronic myelocytic leukemia, miR-181c inhibits chemoresistance by targeting ST8SIA4 [6]. Bioinformatics analysis also identified ST8SIA4 as a common diagnostic marker for atherosclerosis and ankylosing spondylitis, and it is upregulated in samples from both diseases [2].

In conclusion, ST8SIA4 is crucial for germ layer formation during development. Its dysregulation is associated with multiple diseases, especially cancers, where it promotes disease progression. Studies on ST8SIA4 in disease models help in understanding the role of sialylation in disease mechanisms, potentially providing new therapeutic targets for cancer, atherosclerosis, and ankylosing spondylitis.

References:

1. Shu, Xiaodong, Li, Jianjie, Chan, Un In, Deng, Chu-Xia, Xu, Xiaoling. . BRCA1 Insufficiency Induces a Hypersialylated Acidic Tumor Microenvironment That Promotes Metastasis and Immunotherapy Resistance. In Cancer research, 83, 2614-2633. doi:10.1158/0008-5472.CAN-22-3398. https://pubmed.ncbi.nlm.nih.gov/37227919/

2. Ma, Yirong, Lai, Junyu, Wan, Qiang, Zhang, Qinhe, Wu, Jianguang. 2024. Exploring the common mechanisms and biomarker ST8SIA4 of atherosclerosis and ankylosing spondylitis through bioinformatics analysis and machine learning. In Frontiers in cardiovascular medicine, 11, 1421071. doi:10.3389/fcvm.2024.1421071. https://pubmed.ncbi.nlm.nih.gov/39131703/

3. Berger, Ryan P, Sun, Yu Hua, Kulik, Michael, Pierce, Michael, Dalton, Stephen. 2016. ST8SIA4-Dependent Polysialylation is Part of a Developmental Program Required for Germ Layer Formation from Human Pluripotent Stem Cells. In Stem cells (Dayton, Ohio), 34, 1742-52. doi:10.1002/stem.2379. https://pubmed.ncbi.nlm.nih.gov/27074314/

4. Fu, Wan, Yu, Guangcai, Liang, Junnan, Zhu, Hong, Chu, Liang. 2021. miR-144-5p and miR-451a Inhibit the Growth of Cholangiocarcinoma Cells Through Decreasing the Expression of ST8SIA4. In Frontiers in oncology, 10, 563486. doi:10.3389/fonc.2020.563486. https://pubmed.ncbi.nlm.nih.gov/33520692/

5. Ma, Xiaolu, Dong, Weijie, Su, Zhen, Zhou, Huimin, Jia, Li. 2016. Functional roles of sialylation in breast cancer progression through miR-26a/26b targeting ST8SIA4. In Cell death & disease, 7, e2561. doi:10.1038/cddis.2016.427. https://pubmed.ncbi.nlm.nih.gov/28032858/

6. Zhao, Lifen, Li, Yan, Song, Xiaobo, Miao, Yuan, Jia, Li. . Upregulation of miR-181c inhibits chemoresistance by targeting ST8SIA4 in chronic myelocytic leukemia. In Oncotarget, 7, 60074-60086. doi:10.18632/oncotarget.11054. https://pubmed.ncbi.nlm.nih.gov/27527856/

7. Mori, Airi, Hane, Masaya, Niimi, Yuki, Kitajima, Ken, Sato, Chihiro. . Different properties of polysialic acids synthesized by the polysialyltransferases ST8SIA2 and ST8SIA4. In Glycobiology, 27, 834-846. doi:10.1093/glycob/cwx057. https://pubmed.ncbi.nlm.nih.gov/28810663/