| Ubiquitin-conjugating enzyme E2C (UBE2C/UBCH10) is a member of the E2 ubiquitin-conjugating enzyme family that cooperates with the anaphase-promoting complex/cyclosome (APC/C) to catalyze ubiquitin transfer to key mitotic substrates and thereby governs checkpoint control and exit from mitosis. Structurally, UBE2C contains the conserved UBC catalytic domain with an active-site cysteine that forms a thioester with ubiquitin received from E1, and additional sequence elements that direct polyubiquitin chain assembly on preferred lysines in substrates and allow specific pairing with APC/C co-activators such as CDC20 and CDH1. In its canonical cell-cycle role, UBE2C promotes polyubiquitination and proteasomal degradation of short-lived proteins including cyclin B and securin, ensuring timely metaphase–anaphase transition, proper spindle checkpoint satisfaction and ordered mitotic exit; controlled UBE2C activity thus prevents accumulation of mitotic regulators and contributes to genomic stability. Overexpression and amplification of UBE2C disturb this balance: cells with elevated UBE2C ignore spindle checkpoint signals, prematurely degrade checkpoint components, lose mitotic fidelity and acquire chromosomal instability, a hallmark of tumorigenesis. Comprehensive bioinformatics surveys across cancer datasets show that UBE2C mRNA and protein are upregulated in a wide range of solid tumors and hematologic malignancies, with expression levels correlating positively with tumor grade, proliferation indices and poor survival, and high UBE2C predicting increased risk of relapse. Mechanistically, UBE2C in oncogenic contexts extends beyond APC/C regulation to orchestrate broader ubiquitination networks: aberrant activation disrupts APC/C–CDH1 tumor-suppressive fidelity, imposes noncanonical ubiquitin chain topologies and rewires the crosstalk between mono- and polyubiquitination to reshape proteostatic control of signaling proteins. Through these effects, UBE2C integrates growth factor signaling and mTOR-centered metabolic adaptation, influences AKT/GSK3β–β‑catenin and JNK pathway activities described in multiple tumor types, and suppresses cell death programs including autophagy, ferroptosis and DNA damage–induced apoptosis, endowing cancer cells with enhanced plasticity, invasive capacity and resistance to cytotoxic and targeted therapies. In breast, liver, lung, pancreatic and thyroid cancers, UBE2C overexpression drives proliferation, migration and EMT, often via stabilization of upstream receptors such as EGFR and activation of PI3K–AKT or Notch cascades, and its knockdown reduces tumor growth in xenograft models, confirming its functional contribution to malignant progression. |
