Work

Orchestrating cancer stem cell plasticity: deubiquitinases as key regulators of EMT and metabolic rewiring

Year: 2026

Type: review

Abstract: Cancer stem cells (CSCs) drive tumor relapse, metastasis, and multidrug resistance, primarily attributed to their profound phenotypic plasticity. This plasticity largely depends on the dynamic interplay between the epithelial-mesenchymal transition (EMT) program and metabolic reprogramming. However, the molecular mechanisms coordinating these processes remain incompletely elucidated. Emerging evidence suggests that deubiquitinating enzymes (DUBs) may participate in regulating this complex crosstalk. This review systematically elaborates on the functional roles of DUBs in maintaining CSC characteristics within malignancies, exploring how they regulate CSC fate by modulating developmental signaling cascades (Wnt/β-catenin, Hedgehog (Hh), Notch, and TGF-β). By preventing the proteasomal degradation of key transcription factors, DUBs simultaneously drive EMT and coordinate metabolic reprogramming to meet the energetic demands of migrating CSCs. Furthermore, we emphasize the bidirectional feedback loops between EMT-TFs and DUBs, which cooperatively amplify stemness. Finally, selective targeting of the DUB-EMT-metabolism axis may represent a potential strategy for dismantling CSC plasticity and improving responses to anticancer therapies.

Source: Frontiers in Medicine

DOI: 10.3389/fmed.2026.1957953