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Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor LATS Biosensor
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OTUB1 suppresses Hippo signaling via modulating YAP protein in gastric cancer

Cheng Yan1, Huijie Yang2, Peng Su3

  • 1School of Medicine, Key Laboratory of Nano-carbon Modified Film Technology of Henan Province, Diagnostic Laboratory of Animal Diseases, Xinxiang University, Xinxiang, 453003, Henan, China.

Oncogene
|October 21, 2022
PubMed

Insights

Researchers identified OTUB1 as a key factor in gastric cancer progression. This deubiquitinase stabilizes YAP protein, promoting cancer cell stemness and correlating with poor patient survival, offering a potential therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Gastric cancer is a leading cause of cancer mortality worldwide, with limited effective targeted therapies.
  • The Hippo-signaling pathway, particularly the YAP protein, is increasingly recognized for its critical role in gastric cancer development and progression.
  • While YAP phosphorylation is well-studied, its regulation via ubiquitination and deubiquitination is crucial for understanding Hippo signaling in cancer.

Purpose of the Study:

  • To identify critical deubiquitinases (DUBs) regulating the Hippo-signaling pathway in gastric cancer.
  • To elucidate the role of OTUB1 in gastric cancer cell stemness, progression, and YAP protein stability.
  • To investigate the clinical relevance of OTUB1 expression in gastric cancer patients.

Main Methods:

  • Utilized a Deubiquitinase (DUB) siRNA library to screen for key regulators of Hippo signaling.
  • Investigated the interaction between OTUB1 and YAP protein, including specific deubiquitination sites.
  • Analyzed clinical data to correlate OTUB1 expression levels with YAP activity and patient survival outcomes.

Main Results:

  • Discovered OTUB1 as a critical deubiquitinase that stabilizes YAP protein by deubiquitinating it at multiple lysine residues (K90, K280, K343, K494, K497).
  • Demonstrated that OTUB1 facilitates gastric cancer cell stemness and progression.
  • Found elevated OTUB1 expression in gastric cancer tissues, which positively correlated with YAP activity and predicted poor patient survival.

Conclusions:

  • OTUB1 functions as a novel deubiquitinase for the Hippo/YAP axis in gastric cancer.
  • OTUB1-mediated YAP stabilization promotes gastric cancer progression and is associated with adverse clinical outcomes.
  • OTUB1 represents a potential therapeutic target for YAP-driven gastric cancers.

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