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Intramucosal Inoculation of Squamous Cell Carcinoma Cells in Mice for Tumor Immune Profiling and Treatment Response Assessment
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All-Trans Retinoic Acid Promotes a Tumor Suppressive OTUD6B-β-TrCP-SNAIL Axis in Esophageal Squamous Cell Carcinoma

Lei Li1,2, Rui Zhu1, Honghong Zhou1

  • 1State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, P. R. China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|April 10, 2023
PubMed

Insights

OTUD6B deubiquitinase stabilizes β-TrCP, suppressing esophageal squamous cell carcinoma (ESCC). All-trans retinoic acid (ATRA) boosts OTUD6B, inhibiting ESCC growth and enhancing anti-PD-1 therapy response.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • β-TrCP, an E3 ubiquitin ligase, is crucial in esophageal squamous cell carcinoma (ESCC) progression.
  • β-TrCP protein levels, not transcript levels, correlate with ESCC patient prognosis, highlighting the importance of its stability regulators.
  • The specific enzymes regulating β-TrCP stability in ESCC remain largely uncharacterized.

Purpose of the Study:

  • To identify novel regulators of β-TrCP stability in ESCC.
  • To elucidate the role of OTUD6B in ESCC progression and its therapeutic potential.
  • To investigate the effect of all-trans retinoic acid (ATRA) on OTUD6B and its impact on ESCC treatment.

Main Methods:

  • Identification of OTUD6B as a deubiquitinase for β-TrCP using molecular assays.
  • Analysis of OTUD6B expression in ESCC patient samples and correlation with prognosis.
  • In vitro and in vivo studies to evaluate the effect of ATRA on OTUD6B, ESCC growth, and immunotherapy response.

Main Results:

  • OTUD6B was identified as a deubiquitinase of β-TrCP, suppressing ESCC via the OTUD6B-β-TrCP-SNAIL pathway.
  • Low OTUD6B expression in ESCC patients is linked to poor prognosis.
  • ATRA treatment increases OTUD6B translation, reducing ESCC tumor growth and improving anti-PD-1 therapy efficacy.

Conclusions:

  • OTUD6B is a key deubiquitinase for β-TrCP in ESCC, acting as a tumor suppressor.
  • OTUD6B expression level is a prognostic biomarker for ESCC.
  • Combining ATRA with anti-PD-1 immunotherapy presents a promising therapeutic strategy for a subset of ESCC patients.
Keywords:
all-trans retinoic acidanti-PD-1deubiquitinationmetastasistumor-initiating cell propertytumorigenesis

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