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Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay
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CK2α-mediated phosphorylation of DUB3 promotes YAP1 stability and oncogenic functions

Lei Huang1, Yalei Wen2, Qin Guo3

  • 1Department of General Surgery, Guangzhou Red Cross Hospital/State Key Laboratory of Bioactive Molecules and Druggability Assessment/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China/College of Pharmacy, Jinan University, Guangzhou, China.

Cell Death & Disease
|January 18, 2025
PubMed

Insights

Casein kinase II (CK2) regulates Yes-associated protein 1 (YAP1) stability via DUB3. Inhibiting CK2 destabilizes YAP1, suppressing cancer progression, offering new therapeutic strategies for ovarian and other cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Yes-associated protein 1 (YAP1) upregulation drives tumor progression and poor outcomes in various cancers.
  • Targeting YAP1 is therapeutically challenging due to difficulties in direct inhibition.
  • Understanding YAP1 regulation is crucial for developing effective cancer therapies.

Purpose of the Study:

  • Identify novel upstream regulators of YAP1 turnover.
  • Investigate the role of Casein kinase II (CK2) in YAP1 regulation.
  • Elucidate the molecular mechanism linking CK2, DUB3, and YAP1 stability in cancer.

Main Methods:

  • High-throughput screening to identify YAP1 regulators.
  • Pharmacological inhibition (Silmitasertib) and genetic depletion (CK2α) of CK2.
  • In vitro and in vivo studies to assess YAP1 destabilization and oncogenic function suppression.
  • Analysis of DUB3 phosphorylation and its effect on YAP1 deubiquitination.
  • Correlation analysis of CK2α, DUB3, and YAP1 expression in ovarian cancer tissues.

Main Results:

  • CK2 identified as an upstream regulator of YAP1 turnover in multiple cancer types.
  • CK2 inhibition (Silmitasertib or CK2α depletion) destabilizes YAP1 and suppresses its oncogenic functions.
  • DUB3 identified as a deubiquitinase of YAP1, linking CK2 to YAP1 stability.
  • CK2α directly phosphorylates DUB3 at Thr495, promoting YAP1 deubiquitination and stabilization.
  • Phosphorylation-defective DUB3 mutants and CK2 inhibition impair YAP1 stabilization.
  • Upregulated CK2α and DUB3 correlate with YAP1 overexpression in ovarian cancer.

Conclusions:

  • The CK2α-DUB3 axis is critical for YAP1 stabilization and YAP1-driven tumor progression.
  • Targeting the CK2α-DUB3 axis offers a promising therapeutic strategy for YAP1-driven cancers.
  • This axis represents a potential therapeutic vulnerability in ovarian and other lethal cancers.

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