COPS3 (COP9 signalosome subunit 3) is a critical component of the COP9 signalosome complex that regulates ubiquitin-dependent protein degradation through deneddylation of cullin-containing E3 ligases. Beyond this canonical role, COPS3 functions as a prominent oncogene across multiple cancer types. In osteosarcoma, COPS3 amplification occurs in 31% of tumors and correlates with large tumor size and increased metastatic risk 1. COPS3 promotes metastasis through multiple mechanisms: it directly interacts with Raf-1 to activate MEK/ERK signaling and regulate epithelial-mesenchymal transition (EMT) 2, and it interacts with Beclin1 to enhance autophagic flux 2. COPS3 also establishes a positive feedback loop with FOXO3 that promotes cytoprotective autophagy, driving cisplatin resistance 3. Additionally, COPS3 regulates anoikis resistance through the PFKFB3-glycolysis pathway 4. In colorectal cancer, COPS3 depletion suppresses cell proliferation, viability, motility, and EMT via MEK/ERK pathway inhibition 5. COPS3's oncogenic activity suggests it represents a promising therapeutic target for chemoresistant and metastatic cancers.