Pan-cancer proteogenomic interrogation of the Ubiquitin Proteasome System

HighlightsO_LIA pan-cancer proteomic atlas defines the UPS architecture across human cancers C_LIO_LIGenome-wide pQTLs reveal mutation-driven UPS remodeling C_LIO_LILineage- and genotype-specific vulnerabilities created by UPS rewiring C_LIO_LIE3 ligase specificity scores to guide rational design of targeted protein degradation C_LIO_LIAn interactive platform, UbiDash, enables UPS-focused proteogenomic exploration C_LI 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.