Dysregulation of Ubiquitin-Proteasome System in Cancer: A Biochemical Overview

Background: The ubiquitin-proteasome system (UPS) is a pivotal post-translational regulatory mechanism that governs protein homeostasis by orchestrating the selective degradation of short-lived, misfolded, or damaged proteins. Dysregulation of the UPS has emerged as a critical driver of oncogenesis, tumor progression, and therapeutic resistance across a broad spectrum of malignancies. Aberrant activity within this proteolytic network affects cell cycle regulators, apoptosis modulators, transcription factors, and key components of DNA repair pathways, contributing to the malignant phenotype. Methods and Results: This review provides a biochemical overview of UPS components and their pathological alterations in cancer. Central to UPS function is the enzymatic cascade involving E1 activating enzymes, E2 conjugating enzymes, and E3 ligases, which tag substrates with ubiquitin moieties to signal proteasomal degradation. Mutations, overexpression, or loss-of-function in E3 ligases such as MDM2, FBW7, and c-Cbl have been linked to dysregulated degradation of tumor suppressors and stabilization of oncogenic proteins. Similarly, deubiquitinating enzymes (DUBs) like USP7 and CYLD contribute to proteostasis by reversing ubiquitination, and their dysregulation facilitates cancer cell survival. Proteasome subunit alterations and enhanced proteolytic capacity are also hallmarks of many tumor types, promoting unchecked cell proliferation and evasion of apoptosis. Targeted inhibition of the proteasome using agents such as bortezomib has demonstrated clinical efficacy in hematologic malignancies, underscoring the therapeutic potential of modulating UPS activity. Resistance mechanisms, however, necessitate ongoing efforts to develop next-generation proteasome inhibitors and specific E3 or DUB modulators. Conclusion: The UPS plays a central biochemical role in regulating protein turnover and cellular signaling fidelity. Its dysregulation in cancer underlies key aspects of tumor biology, representing both a mechanistic insight into malignancy and a promising avenue for targeted therapeutic intervention.