Abstract
Components of the Ubiquitin Proteasome System (UPS) are attractive candidates for targeted protein degradation therapies owing to their key roles in maintaining protein homeostasis in healthy and malignant cells. How cancer driver mutations rewire UPS components to support tumor growth and survival remains incompletely understood. By mapping tissue- and cancer-specific expression of UPS components across more than 20 tissues and 10 tumor types using harmonized multiomic datasets, we present an integrated pan-cancer proteogenomic analysis focused on E3 ubiquitin ligases. These analyses uncovered (1) mutation-associated UPS protein level changes; (2) clinically actionable E3s based on recurrent alterations, tissue-enriched expression, and prognostic value; and (3) E3 regulatory networks based on co-expression, co-dependency, and protein-protein interactions. We also introduce UbiDash, an interactive platform for exploring UPS alterations across cancers. This study identifies clinically relevant E3s and mutation-defined proteostatic dependencies and provides resource for mechanistic insight and therapeutic prioritization of UPS components in cancer.