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Peer-reviewedCC BY 4.0Cells

The SKP2–Substrate Axis in Hematological Malignancies: Mechanisms of Oncogenesis and Opportunities for Targeted Therapy

  • Yueying Zhang1,2
  • Omar Faruq1,3
  • Mariusz Shrestha3
  • Shamila D. Alipoor4
  • Hong Chang1,3
4 affiliations
  1. 1Laboratory Medicine Program, Department of Laboratory Hematology, University Health Network, Toronto, ON M5G 2C4, Canada
  2. 2Department of Pathophysiology, College of Clinical and Basic Medicine, Shandong First Medical University, Jinan 250017, China
  3. 3Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada
  4. 4Department of Biomedical and Clinical Sciences, Linköping University, SE-581 83 Linköping, Sweden
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Abstract

S-phase kinase-associated protein 2 (SKP2), a key substrate-recognition subunit of the Skp1-Cul1-F-box (SCF) E3 ubiquitin ligase complex, promotes the ubiquitin–proteasome-mediated degradation of tumor suppressors such as p27Kip1 and p21(Cip1/Waf1). Through these activities, SKP2 regulates critical cellular processes, including cell cycle progression, apoptosis, metabolic reprogramming, maintenance of cancer stem cell stemness, and contributes to the pathogenesis, therapeutic resistance, and clinical progression of hematological malignancies. Recent advances in protein degradation technologies and regulatory network analysis have highlighted SKP2 and its substrate interactions as promising targets for precision therapies. In this review, we examine the biological functions of SKP2 and regulatory mechanisms governing its substrate spectrum across hematological malignancies, including acute myeloid leukemia, chronic myeloid leukemia, B/NK/T-cell lymphoma, and multiple myeloma. We further review currently available SKP2-targeted therapeutic strategies, including small-molecule inhibitors, molecular glue degraders, and proteolysis-targeting chimeras (PROTACs), and discuss SKP2-related prognostic biomarkers in hematological malignancies. Finally, we outline the key challenges and future directions to guide the development of SKP2-centered therapeutic approaches.

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Cite

BibTeXRIS
BibTeX
@article{zhang2026skp2substrate,
  title = {{The SKP2–Substrate Axis in Hematological Malignancies: Mechanisms of Oncogenesis and Opportunities for Targeted Therapy}},
  author = {Yueying Zhang and Omar Faruq and Mariusz Shrestha and Shamila D. Alipoor and Hong Chang},
  journal = {Cells},
  year = {2026},
  month = sep,
  doi = {10.3390/cells15191796},
  url = {https://www.mdpi.com/2073-4409/15/19/1796},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - The SKP2–Substrate Axis in Hematological Malignancies: Mechanisms of Oncogenesis and Opportunities for Targeted Therapy
AU  - Yueying Zhang
AU  - Omar Faruq
AU  - Mariusz Shrestha
AU  - Shamila D. Alipoor
AU  - Hong Chang
PY  - 2026
DA  - 2026/09/30
JO  - Cells
DO  - 10.3390/cells15191796
UR  - https://www.mdpi.com/2073-4409/15/19/1796
AB  - S-phase kinase-associated protein 2 (SKP2), a key substrate-recognition subunit of the Skp1-Cul1-F-box (SCF) E3 ubiquitin ligase complex, promotes the ubiquitin–proteasome-mediated degradation of tumor suppressors such as p27Kip1 and p21(Cip1/Waf1). Through these activities, SKP2 regulates critical cellular processes, including cell cycle progression, apoptosis, metabolic reprogramming, maintenance of cancer stem cell stemness, and contributes to the pathogenesis, therapeutic resistance, and clinical progression of hematological malignancies. Recent advances in protein degradation technologies and regulatory network analysis have highlighted SKP2 and its substrate interactions as promising targets for precision therapies. In this review, we examine the biological functions of SKP2 and regulatory mechanisms governing its substrate spectrum across hematological malignancies, including acute myeloid leukemia, chronic myeloid leukemia, B/NK/T-cell lymphoma, and multiple myeloma. We further review currently available SKP2-targeted therapeutic strategies, including small-molecule inhibitors, molecular glue degraders, and proteolysis-targeting chimeras (PROTACs), and discuss SKP2-related prognostic biomarkers in hematological malignancies. Finally, we outline the key challenges and future directions to guide the development of SKP2-centered therapeutic approaches.
SN  - 2073-4409
ER  -