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Inhibiting the Otub1/phosphorylated STAT3 axis for the treatment of non-small cell lung cancer

Zi-Yang Liu1, Ya-Wen Zhang2, Hai-Xia Zhuang1

  • 1The Key Laboratory of Advanced Interdisciplinary Studies, The First Affiliated Hospital of Guangzhou Medical University & Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China.

Acta Pharmacologica Sinica
|August 28, 2024
PubMed

Insights

Otub1 deubiquitinates and stabilizes phosphorylated STAT3 (pSTAT3-Y705), promoting non-small cell lung cancer (NSCLC) survival. Crizotinib inhibits this axis, suppressing NSCLC growth and xenograft tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Signal transducer and activator of transcription 3 (STAT3) is a key target in non-small cell lung cancer (NSCLC).
  • STAT3 activity is regulated by phosphorylation at tyrosine 705 (pSTAT3-Y705), but its precise modulation remains unclear.
  • Deubiquitinases (Dubs) play critical roles in protein stability and cellular processes.

Purpose of the Study:

  • To identify deubiquitinases that regulate pSTAT3-Y705.
  • To investigate the role of the Otub1/pSTAT3-Y705 axis in NSCLC.
  • To identify potential therapeutic agents targeting this axis.

Main Methods:

  • Screening of deubiquitinase libraries.
  • Biochemical assays to assess protein interactions and ubiquitination.
  • Luciferase-based drug screening assay.
  • In vitro cell proliferation and apoptosis assays.
  • In vivo NSCLC xenograft studies.

Main Results:

  • Otub1 was identified as a deubiquitinase that binds to pSTAT3-Y705, preventing its K48-linked ubiquitination and degradation.
  • Otub1 enhances STAT3 transcriptional activity, promoting NSCLC cell survival.
  • Crizotinib was found to inhibit Otub1-mediated deubiquitination of pSTAT3-Y705, leading to its degradation.
  • Crizotinib suppressed proliferation and colony formation in ALK-intact NSCLC cells and reduced NSCLC xenograft growth.

Conclusions:

  • Otub1 is the first identified deubiquitinase of pSTAT3-Y705.
  • The Otub1/pSTAT3-Y705 axis represents a novel therapeutic target for NSCLC.
  • Crizotinib demonstrates potential as a treatment for NSCLC by targeting the Otub1/pSTAT3-Y705 pathway.
Keywords:
CrizotinibOtub1STAT3non-small cell lung cancer

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