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Genomic and functional characterizations of phosphodiesterase subtype 4D in human cancers

De-Chen Lin1, Liang Xu, Ling-Wen Ding

  • 1Division of Hematology/Oncology, Cedars-Sinai Medical Center, University of California School of Medicine, Los Angeles, CA 90048, USA. dchlin11@gmail.com

Proceedings of the National Academy of Sciences of the United States of America
|March 29, 2013
PubMed

Insights

Phosphodiesterase 4D (PDE4D) gene deletions unexpectedly increased its protein levels in tumors. PDE4D depletion inhibited cancer cell growth, suggesting PDE4D is a tumor promoter and potential therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Genomic dosage is crucial for cancer gene discovery.
  • Phosphodiesterase subtype 4D (PDE4D) gene deletions were observed in solid tumors.
  • Microdeletions did not lead to loss of PDE4D gene products.

Purpose of the Study:

  • Investigate the role of PDE4D in cancer.
  • Determine if PDE4D is a viable therapeutic target.

Main Methods:

  • Genomic analysis of 5,569 primary solid tumors.
  • Immunohistochemistry staining of 165 tumor samples.
  • PDE4D depletion using shRNAs.
  • PDE4D isoform expression analysis.
  • In vitro and in vivo cancer cell proliferation assays.
  • Treatment with a specific PDE4D inhibitor (26B).

Main Results:

  • PDE4D gene was homozygously deleted in 3.56% of tumors.
  • PDE4D protein levels were upregulated in tumors compared to normal tissues.
  • PDE4D depletion induced apoptosis and growth inhibition in multiple cancer cell lines.
  • Antitumor effects were linked to BIM induction and MITF downregulation.
  • PDE4D inhibition preferentially affected cancer cells over nonmalignant cells.

Conclusions:

  • PDE4D acts as a tumor-promoting factor despite genomic deletions.
  • PDE4D is a potential therapeutic target for various cancers.
  • Targeting PDE4D with inhibitors shows promise for cancer treatment.

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