UBE2C-orchestrated ubiquitination networks in cancer progression and therapy resistance.

Ubiquitination is a central regulatory mechanism governing protein homeostasis, signaling integration, and cellular adaptation, and its dysregulation is increasingly recognized as a fundamental driver of cancer progression and therapy resistance. Ubiquitin-conjugating enzyme E2C (UBE2C) has traditionally been viewed as a cell cycle-associated factor that cooperates with the anaphase-promoting complex/cyclosome (APC/C) to control mitotic progression. However, mounting evidence now indicates that UBE2C plays a far broader and more active role in malignant transformation. Rather than acting as a passive executor of ubiquitin transfer, UBE2C contributes to ubiquitination network remodeling in cancer contexts that coordinate oncogenic signaling, metabolic reprogramming, cell fate decisions, invasion, metastasis, and therapeutic resistance across diverse cancer types. In this review, we synthesize recent mechanistic and translational studies demonstrating how aberrant UBE2C activation reshapes ubiquitin signaling at multiple levels. UBE2C disrupts APC/C-CDH1 tumor-suppressive fidelity, imposes non-canonical ubiquitin chain topologies, and orchestrates crosstalk between mono- and polyubiquitination to rewire proteostatic control. Through these mechanisms, UBE2C integrates growth factor signaling, mTOR-centered metabolic adaptation, redox homeostasis, and suppression of cell death programs, including autophagy, ferroptosis, and DNA damage-induced apoptosis. This coordinated reprogramming endows cancer cells with enhanced plasticity, metastatic competence, and resilience to cytotoxic and targeted therapies. We further discuss emerging strategies for therapeutically targeting UBE2C, including direct inhibition, exploitation of synthetic lethal vulnerabilities, and biomarker-guided patient stratification. Collectively, this review redefines UBE2C as a systems-level regulator of ubiquitin-dependent cancer biology and highlights its potential as both a therapeutic target and a biomarker for precision oncology.