SIAH2 Gene - E3 Ubiquitin Ligase in Hypoxia and Cancer

SIAH2 (Seven in absentia homolog 2) encodes an E3 ubiquitin-protein ligase that targets proteins for proteasomal degradation. It plays a central role in the cellular response to hypoxia by regulating the stability of hypoxia-inducible factor (HIF) prolyl hydroxylases (PHDs), thereby modulating HIF-1α levels. SIAH2 also participates in apoptosis, cell cycle control, and DNA damage response. Dysregulation of SIAH2 is implicated in multiple cancers, including breast, lung, and prostate cancer, as well as neurodegenerative disorders.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Hypoxia-inducible factor (HIF) pathway

• Ubiquitin-mediated proteolysis (KEGG: hsa04120)

• p53 signaling pathway

• Apoptosis

SIAH2 is a 324-amino acid E3 ubiquitin ligase containing an N-terminal RING finger domain and a C-terminal substrate-binding domain. It mediates ubiquitination and degradation of target proteins such as PHD3, DCC, and synphilin-1. Under normoxia, SIAH2 promotes PHD degradation, leading to HIF-1α stabilization and activation of hypoxia-responsive genes. SIAH2 also interacts with TRAF2 and regulates JNK signaling. Its expression is induced by hypoxia and DNA damage. Structural studies show that SIAH2 forms homodimers and heterodimers with SIAH1.