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 multiple pathways such as the SIAH2-HIF-1 axis, PI3K/AKT signaling pathway, and regulation of DNA end resection and replication fork recovery [1,2,3,7]. It also participates in controlling the levels of various proteins through ubiquitination and proteasomal degradation, which is crucial for numerous biological processes [1,6,7]. Genetic models like gene knockout (KO) mice are valuable for studying Siah2's functions.

In Siah2 -/- mice, the growth of BRAF-mutant melanoma cells is inhibited, accompanied by increased intra-tumoral activated T cells and decreased Treg proliferation and infiltration. This shows that Siah2 controls melanoma development by regulating Treg recruitment and cell cycle progression, and Siah2 loss can sensitize melanoma to anti-PD-1 therapy [4]. In hepatocellular carcinoma, Siah2 knockdown promotes CD8+ T cell proliferation and tumor cell ferroptosis, inhibiting tumor growth. Siah2 also induces ubiquitination and degradation of ACSL4, which is required for CD8+ T cell-mediated ferroptosis of HCC cells [5].

In conclusion, Siah2 is a key E3 ubiquitin ligase involved in regulating various biological processes and diseases, especially cancer. KO mouse models have revealed its role in tumor development and response to therapy, providing important insights into the underlying mechanisms and potential therapeutic targets for cancer treatment.