2. Academic Validation
  3. SKP2 promotes the metastasis of pancreatic ductal adenocarcinoma by suppressing TRIM21-mediated PSPC1 degradation

SKP2 promotes the metastasis of pancreatic ductal adenocarcinoma by suppressing TRIM21-mediated PSPC1 degradation

  • Cancer Lett. 2024 Feb 13:216733. doi: 10.1016/j.canlet.2024.216733.
Jiahui Yuan 1,  Zeyao Zhu 2,  Pingping Zhang 3,  Milad Ashrafizadeh 1,  A M Abd El-Aty 4,  Ahmet Hacımüftüoğlu 5,  Christina Susanne Linnebacher 6,  Michael Linnebacher 6,  Sethi Gautam 7,  Peng Gong 8,  Xianbin Zhang 9
Affiliations

Affiliations

  • 1 Department of General Surgery and Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Shenzhen University General Hospital, Shenzhen University, Shenzhen, Guangdong, 518055, China; International Association for Diagnosis and Treatment of Cancer, Shenzhen, Guangdong, 518055, China.
  • 2 School of Life Sciences, Southern University of Science and Technology, Shenzhen, Guangdong, 518055, China.
  • 3 Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China.
  • 4 Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza, 12211, Egypt; Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum, 25070, Turkey.
  • 5 Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum, 25070, Turkey.
  • 6 Clinic of General Surgery, Molecular Oncology and Immunotherapy, Rostock University Medical Center, Rostock, 18059, Germany.
  • 7 Department of Pharmacology and NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
  • 8 Department of General Surgery and Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Shenzhen University General Hospital, Shenzhen University, Shenzhen, Guangdong, 518055, China.
  • 9 Department of General Surgery and Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Shenzhen University General Hospital, Shenzhen University, Shenzhen, Guangdong, 518055, China; International Association for Diagnosis and Treatment of Cancer, Shenzhen, Guangdong, 518055, China. Electronic address: [email protected].
PMID: 38360141 DOI: 10.1016/j.canlet.2024.216733
Abstract

Despite significant advances in diagnostic techniques and treatment approaches, the prognosis of pancreatic ductal adenocarcinoma (PDAC) is still poor. Previous studies have reported that S-phase kinase-associated protein 2 (SKP2), a subunit of the SCF E3 ubiquitin ligase complex, is engaged in the malignant biological behavior of some tumor entities. However, SKP2 has not been fully investigated in PDAC. In the present study, it was observed that high expression of SKP2 significantly correlates with decreased survival time. Further experiments suggested that SKP2 promotes metastasis by interacting with the putative transcription factor paraspeckle component 1 (PSPC1). According to the results of coimmunoprecipitation and ubiquitination assays, SKP2 depletion resulted in the polyubiquitination of PSPC1, followed by its degradation. Furthermore, the SKP2-mediated ubiquitination of PSPC1 partially depended on the activity of the E3 ligase TRIM21. In addition, inhibition of the SKP2/PSPC1 axis by SMIP004, a traditional inhibitor of SKP2, impaired the migration of PDAC cells. In summary, this study provides novel insight into the mechanisms involved in PDAC malignant progression. Targeting the SKP2/PSPC1 axis is a promising strategy for the treatment of PDAC.

Keywords

Metastasis; PDAC; PSPC1; SKP2; Ubiquitin-mediated degradation.

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