ArticleProceedings of the National Academy of Sciences of the United States of America2013
Genomic and functional characterizations of phosphodiesterase subtype 4D in human cancers.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 72 citations in OpenAlex.
- β-Adrenergic Signaling Promotes Anti-Tumor Immunity in TP53-mutant Oral Squamous Cell Carcinoma.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Pan-Cancer Analysis of Cyclic Nucleotide Phosphodiesterases (PDEs) Expression, Variation, and Prognostic Significance.ACS omega · 2025Article
- Targeted protein degradation of PDE4 shortforms by a novel proteolysis targeting chimera.The FEBS journal · 2025Article
- Targeting Phosphodiesterase 4 in Gastrointestinal and Liver Diseases: From Isoform-Specific Mechanisms to Precision Therapeutics.Biomedicines · 2025Review
- Phosphodiesterase 7: a potential novel therapeutic target in ovarian cancer.Frontiers in pharmacology · 2025Article
- PDE4D drives rewiring of the MAPK pathway in BRAF-mutated melanoma resistant to MAPK inhibitors.Cell communication and signaling : CCS · 2024Article
- Toxic PARP trapping upon cAMP-induced DNA damage reinstates the efficacy of endocrine therapy and CDK4/6 inhibitors in treatment-refractory ER+ breast cancer.Nature communications · 2023Article
- PI3K signalling at the intersection of cardio-oncology networks: cardiac safety in the era of AI.Cellular and molecular life sciences : CMLS · 2022Review
- ZL-n-91, a specific Phosphodiesterase-4 inhibitor, suppresses the growth of triple-negative breast cancer.Investigational new drugs · 2022Article
- IL-27 Enhances γδ T Cell-Mediated Innate Resistance to Primary Hookworm Infection in the Lungs.Journal of immunology (Baltimore, Md. : 1950) · 2022Article
- Review
- Constructing gene regulatory networks using epigenetic data.NPJ systems biology and applications · 2021Article
- The MAVS Immune Recognition Pathway in Viral Infection and Sepsis.Antioxidants & redox signaling · 2021Review
- Oncogenic enhancers drive esophageal squamous cell carcinogenesis and metastasis.Nature communications · 2021Article
- Eggmanone Effectively Overcomes Prostate Cancer Cell Chemoresistance.Biomedicines · 2021Article
- Phosphodiesterase 4D Depletion/Inhibition Exerts Anti-Oncogenic Properties in Hepatocellular Carcinoma.Cancers · 2021Article
- Cyclic adenosine monophosphate (cAMP) signaling in melanocyte pigmentation and melanomagenesis.Pigment cell & melanoma research · 2021Review
- Nanomedicine: A Diagnostic and Therapeutic Approach to COVID-19.Frontiers in medicine · 2021Review
- Cyclic AMP-hydrolyzing phosphodiesterase inhibitors potentiate statin-induced cancer cell death.Molecular oncology · 2020Article
- Article
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Authors and funding
21 authors at 11 institutions in 3 countries.
Funding
Abstract
Discovery of cancer genes through interrogation of genomic dosage is one of the major approaches in cancer research. In this study, we report that phosphodiesterase subtype 4D (PDE4D) gene was homozygously deleted in 198 cases of 5,569 primary solid tumors (3.56%), with most being internal microdeletions. Unexpectedly, the microdeletions did not result in loss of their gene products. Screening PDE4D expression in 11 different types of primary tumor samples (n = 165) with immunohistochemistry staining revealed that its protein levels were up-regulated compared with corresponding nontransformed tissues. Importantly, depletion of endogenous PDE4D with three independent shRNAs caused apoptosis and growth inhibition in multiple types of cancer cells, including breast, lung, ovary, endometrium, gastric, and melanoma, which could be rescued by reexpression of PDE4D. We further showed that antitumor events triggered by PDE4D suppression were lineage-dependently associated with Bcl-2 interacting mediator of cell death (BIM) induction and microphthalmia-associated transcription factor (MITF) down-regulation. Furthermore, ectopic expression of the PDE4D short isoform, PDE4D2, enhanced the proliferation of cancer cells both in vitro and in vivo. Moreover, treatment of cancer cells with a unique specific PDE4D inhibitor, 26B, triggered massive cell death and growth retardation. Notably, these antineoplastic effects induced by either shRNAs or small molecule occurred preferentially in cancer cells but not in nonmalignant epithelial cells. These results suggest that although targeted by genomic homozygous microdeletions, PDE4D functions as a tumor-promoting factor and represents a unique targetable enzyme of cancer cells.
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