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Screening for YAP Inhibitors Identifies Statins as Modulators of Fibrosis
- Source :
- Am J Respir Cell Mol Biol
- Publication Year :
- 2020
- Publisher :
- American Thoracic Society, 2020.
-
Abstract
- Idiopathic pulmonary fibrosis is a lung disease with limited therapeutic options that is characterized by pathological fibroblast activation and aberrant lung remodeling with scar formation. YAP (Yes-associated protein) is a transcriptional coactivator that mediates mechanical and biochemical signals controlling fibroblast activation. In this study, we developed a high-throughput small-molecule screen for YAP inhibitors in primary human lung fibroblasts. Multiple HMG-CoA (hydroxymethylglutaryl-coenzyme A) reductase inhibitors (statins) were found to inhibit YAP nuclear localization via induction of YAP phosphorylation, cytoplasmic retention, and degradation. We further show that the mevalonate pathway regulates YAP activation, and that simvastatin treatment reduces fibrosis markers in activated human lung fibroblasts and in the bleomycin mouse model of pulmonary fibrosis. Finally, we show that simvastatin modulates YAP in vivo in mouse lung fibroblasts. Our results highlight the potential of small-molecule screens for YAP inhibitors and provide a mechanism for the antifibrotic activity of statins in idiopathic pulmonary fibrosis.
- Subjects :
- Pulmonary and Respiratory Medicine
Cytoplasm
Simvastatin
Pulmonary Fibrosis
Clinical Biochemistry
Mevalonic Acid
Cell Cycle Proteins
Bleomycin
Small Molecule Libraries
Idiopathic pulmonary fibrosis
chemistry.chemical_compound
Mice
Fibrosis
Pulmonary fibrosis
medicine
Animals
Humans
Fibroblast
Molecular Biology
Original Research
Adaptor Proteins, Signal Transducing
Cell Nucleus
Hippo signaling pathway
biology
business.industry
YAP-Signaling Proteins
Cell Biology
Fibroblasts
medicine.disease
Phosphoproteins
medicine.anatomical_structure
chemistry
HMG-CoA reductase
biology.protein
Cancer research
Mevalonate pathway
Acyl Coenzyme A
Hydroxymethylglutaryl-CoA Reductase Inhibitors
business
Biomarkers
Signal Transduction
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Am J Respir Cell Mol Biol
- Accession number :
- edsair.doi.dedup.....b69e7ff705685e150c6c5d62f81c340b