THE UBIQUITIN-PROTEASOME SYSTEM IN CANCER: MECHANISMS, TARGETS AND THERAPEUTIC POTENTIAL.

Abstract

The ubiquitin-proteasome system (UPS) is the central mechanism for regulated intracellular protein degradation in eukaryotic cells, controlling essential biological processes including cell cycle progression, DNA repair, apoptosis, and signal transduction. Through a hierarchical enzymatic cascade, ubiquitin is covalently attached to substrate proteins, often as polyubiquitin chains, marking them for selective degradation by the 26S proteasome. Dysregulation of this system is a hallmark of cancer, where altered ubiquitination dynamics can drive malignant transformation by promoting the degradation of tumor suppressors or stabilizing oncogenic proteins. Deubiquitinating enzymes (DUBs), particularly the ubiquitin-specific protease (USPs) family, reverse ubiquitination and help maintain protein homeostasis. Many USPs are aberrantly expressed or genetically altered in tumors, contributing to oncogenic signaling, resistance to apoptosis, and therapy evasion. This review presents a comprehensive overview of the architecture and function of the UPS, focusing on ubiquitination mechanisms, proteasomal activity, and context-dependent roles of DUBs in cancer. Here, we highlight emerging therapeutic strategies that target various UPS components, including FDA-approved proteasome inhibitors, inhibitors of E3 ligase function, PROTAC-based protein degradation, and small-molecule USP inhibitors. While drugging DUBs remains challenging due to issues of specificity and toxicity, advances in structure-based design and ubiquitin code mapping are accelerating progress. Overall, the UPS is a key regulatory hub in cancer biology and a promising target in precision oncology. Therapeutic modulation of this pathway offers new opportunities for destabilizing oncogenic networks and overcoming resistance mechanisms in cancer.