Ubiquitination in cancer: mechanisms, signaling networks and potential therapeutic opportunities

Abstract

Protein ubiquitination is among the most important posttranslational modifications in eukaryotes. It precisely regulates protein stability and cellular signaling through the ubiquitin‒proteasome system (UPS). A dynamic equilibrium network formed by the E1-E2-E3 enzymatic cascade and deubiquitinating enzymes (DUBs) plays a central role in cell cycle regulation, DNA damage repair, and signal transduction. In tumorigenesis and cancer progression, the UPS regulates key factors such as p53 and p27 to control cell proliferation and apoptosis. It is involved in the activation of oncogenic pathways, including the PI3K/Akt, Wnt/β-catenin, and NF-κB pathways, and regulates cancer stem cell maintenance and tumor immune microenvironment remodeling. On the basis of these mechanisms, significant progress has been made in therapeutic strategies targeting the UPS. Proteasome inhibitors have become standard treatments for multiple myeloma. Proteolysis-targeting chimera (PROTAC) technology overcomes the limitations of “undruggable” targets and enables the specific degradation of pathogenic proteins such as the androgen receptor (AR) and estrogen receptor (ER). Molecular glue degraders exert antitumor effects by reshaping the substrate recognition interface of E3 ligases. E3 ligase inhibitors and DUB inhibitors are also entering clinical development. However, the selective toxicity, pharmacokinetic limitations of PROTACs, and acquired resistance remain major challenges. Future research should focus on optimizing drug design and delivery strategies to reduce systemic toxicity and establish a ubiquitination biomarker-guided precision medicine framework. ∙ Ubiquitination is a reversible posttranslational modification regulated by the E1-E2-E3 enzymatic cascade and deubiquitinases (DUBs). Distinct ubiquitin chain linkages (e.g., K48-, K63-, and M1-linked chains) determine the fate of substrate proteins. ∙ The ubiquitin system regulates core cell cycle regulators, including cyclins, cyclin-dependent kinase inhibitors (CKIs), and the tumor suppressor p53, thereby controlling cell cycle progression or arrest. ∙ Major protumorigenic signaling pathways, including the PI3K/Akt, Wnt/β-catenin, and NF-κB pathways, are extensively regulated by ubiquitination. ∙ Ubiquitination contributes to the maintenance of cancer stem cell (CSC) stemness. ∙ In the tumor microenvironment (TME), ubiquitination regulates immune evasion, immune cell function, and stromal cell reprogramming. ∙ Strategies targeting the ubiquitin system, such as proteasome inhibitors, E3 ligases and DUB modulators, and targeted protein degradation technologies, such as proteolysis-targeting chimeras (PROTACs) and molecular glue degraders (MGDs), have emerged as rapidly advancing therapeutic strategies in cancer. ∙ Therapies targeting the ubiquitin‒proteasome system (UPS) are limited by selective toxicity, the limited druggability of PROTACs, and acquired resistance.