Siah2, or Seven in absentia homolog 2, is a RING E3 ubiquitin ligase. It plays a vital role in tumorigenesis and cancer progression, and is involved in regulating multiple cellular processes. Siah2 has been linked to pathways such as the PI3K/AKT signaling pathway and the SIAH2-HIF-1 axis [1,2,3]. It is also subject to complex regulation, especially phosphorylation by protein kinases, which affects its stability and activity [1,2]. Genetic models, like gene knockout (KO) mouse models, are valuable for studying Siah2's functions.

In Siah2 -/- mice, the growth of BRAF-mutant melanoma cells is inhibited, with increased intra-tumoral activated T cells and decreased Treg proliferation and infiltration. This indicates Siah2 regulation of Treg recruitment and cell cycle progression controls melanoma development, and Siah2 loss sensitizes melanoma to anti-PD-1 therapy [4]. In hepatocellular carcinoma, Siah2 knockdown promoted CD8+ T cell proliferation and tumor cell ferroptosis, inhibiting tumor growth. Siah2 induced ubiquitination of ACSL4, which is required for CD8+ T cell-mediated ferroptosis of HCC cells [5].

In conclusion, Siah2 is a key regulator in multiple biological processes, especially in tumor-related events. KO mouse models have revealed its role in controlling tumor development, particularly in melanoma and hepatocellular carcinoma, highlighting its potential as a therapeutic target in cancer treatment.

References:

1. Li, Kailang, Li, Jinyun, Ye, Meng, Jin, Xiaofeng. 2021. The role of Siah2 in tumorigenesis and cancer therapy. In Gene, 809, 146028. doi:10.1016/j.gene.2021.146028. https://pubmed.ncbi.nlm.nih.gov/34687788/

2. Xu, Dazhong, Li, Cen. 2021. Regulation of the SIAH2-HIF-1 Axis by Protein Kinases and Its Implication in Cancer Therapy. In Frontiers in cell and developmental biology, 9, 646687. doi:10.3389/fcell.2021.646687. https://pubmed.ncbi.nlm.nih.gov/33842469/

3. Hu, Yongbo, He, Yiming, Liu, Wei, Su, Yu, Xiao, Bin. 2022. SIAH2 regulates colorectal cancer tumorigenesis via PI3K/ATK signaling pathway. In Tissue & cell, 78, 101878. doi:10.1016/j.tice.2022.101878. https://pubmed.ncbi.nlm.nih.gov/35926257/

4. Scortegagna, Marzia, Hockemeyer, Kathryn, Dolgalev, Igor, Aifantis, Ioannis, Ronai, Ze'ev A. 2020. Siah2 control of T-regulatory cells limits anti-tumor immunity. In Nature communications, 11, 99. doi:10.1038/s41467-019-13826-7. https://pubmed.ncbi.nlm.nih.gov/31911617/

5. Shu, Fangzheng, Shi, Yuhua, Shan, Xiangxiang, Fan, Rengen, Xue, Wanjiang. . SIAH2-Mediated Degradation of ACSL4 Inhibits the Anti-Tumor Activity of CD8+ T Cells in Hepatocellular Carcinoma. In Critical reviews in eukaryotic gene expression, 34, 1-13. doi:10.1615/CritRevEukaryotGeneExpr.2024051981. https://pubmed.ncbi.nlm.nih.gov/38842200/