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Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay
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Phosphorylation of USP33 by CDK1 stabilizes the mTORC2 component SIN1

Yalei Wen1,2, Caishi Zhang3, Mingchao Liang4

  • 1Research Institute for Maternal and Child Health, The Affiliated Guangdong Second Provincial General Hospital, Postdoctoral Research Station of Traditional Chinese Medicine, School of Pharmacy, Jinan University, Guangzhou, China.

Cell Death & Disease
|July 22, 2025
PubMed

Insights

Elevated SIN1 expression drives pancreatic cancer chemoresistance by stabilizing mTORC2. Targeting the CDK1-USP33 axis destabilizes SIN1, enhancing chemotherapy sensitivity and improving patient survival outcomes in pancreatic ductal adenocarcinoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Chemoresistance remains a significant hurdle in effective cancer therapy.
  • The mammalian target of rapamycin complex 2 (mTORC2) pathway, regulated by SIN1, is crucial for cellular processes.
  • Understanding SIN1's role in pancreatic ductal adenocarcinoma (PDAC) is vital for therapeutic development.

Purpose of the Study:

  • To investigate the role of SIN1 in PDAC chemoresistance.
  • To identify key regulatory mechanisms of SIN1 stabilization in PDAC.
  • To evaluate the therapeutic potential of targeting the identified regulatory axis.

Main Methods:

  • Correlation analysis of SIN1 expression with patient survival in PDAC.
  • Assessment of tumor growth and chemosensitivity following SIN1 deletion in PDAC models.
  • Identification and functional validation of USP33 as a SIN1 deubiquitinase.
  • Investigation of CDK1-mediated phosphorylation of USP33 and its impact on SIN1.
  • Analysis of CDK1, USP33, and SIN1 expression correlations in PDAC tissues.

Main Results:

  • Elevated SIN1 expression in PDAC correlates with poorer patient survival.
  • SIN1 deletion reduces tumor growth and increases sensitivity to chemotherapy in PDAC.
  • USP33 deubiquitinates and stabilizes SIN1, promoting chemoresistance via mTORC2-AKT activation.
  • CDK1 phosphorylates USP33, enhancing its activity towards SIN1 and driving PDAC progression.
  • A significant positive correlation exists between CDK1, USP33, and SIN1 expression in PDAC tissues.

Conclusions:

  • SIN1 stabilization by the USP33 deubiquitinase, further regulated by CDK1, is a key mechanism driving chemoresistance in PDAC.
  • Targeting the CDK1-USP33 axis offers a potential therapeutic strategy to destabilize SIN1.
  • This approach may overcome chemoresistance in PDAC and holds promise for other aggressive cancers.

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