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Peer-reviewedCC BYFrontiers in medicine

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

  • Tao Qin1
  • Yupeng Wang2
  • Minhao Li3
  • Qian Liu1
  • Lu Yue4
  • Shuzhen Liang5
  • Duoping Sun6
6 affiliations
  1. 1The Third Clinical School of Medical Science, Qingdao University, Qingdao Municipal Hospital , ,
  2. 2Pharmacy Department, Qingdao Eighth People’s Hospital , ,
  3. 3Supervision Office (Ministry of Justice), Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Hospital) , ,
  4. 4Department of Oncology, Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital) , ,
  5. 5Central Laboratories, Qingdao Municipal Hospital, University of Health and Rehabilitation Sciences , ,
  6. 6Department of Radiation Oncology, Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital) , ,
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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.

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Cite

BibTeXRIS
BibTeX
@article{qin2026orchestrating,
  title = {{Orchestrating cancer stem cell plasticity: deubiquitinases as key regulators of EMT and metabolic rewiring}},
  author = {Tao Qin and Yupeng Wang and Minhao Li and Qian Liu and Lu Yue and Shuzhen Liang and Duoping Sun},
  journal = {Frontiers in medicine},
  year = {2026},
  month = oct,
  doi = {10.3389/fmed.2026.1957953},
  url = {https://europepmc.org/article/PMC/PMC13720446},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Orchestrating cancer stem cell plasticity: deubiquitinases as key regulators of EMT and metabolic rewiring
AU  - Tao Qin
AU  - Yupeng Wang
AU  - Minhao Li
AU  - Qian Liu
AU  - Lu Yue
AU  - Shuzhen Liang
AU  - Duoping Sun
PY  - 2026
DA  - 2026/10/16
JO  - Frontiers in medicine
DO  - 10.3389/fmed.2026.1957953
UR  - https://europepmc.org/article/PMC/PMC13720446
AB  - 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.
SN  - 2296-858X
ER  -