Scientific reports, 2019-03, Vol.9 (1), p.5197-14, Article 5197
2019
Details
- Autor(en) / Beteiligte
- Titel
- Activin A regulates the epidermal growth factor receptor promoter by activating the PI3K/SP1 pathway in oral squamous cell carcinoma cells
- Ist Teil von
- Scientific reports, 2019-03, Vol.9 (1), p.5197-14, Article 5197
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2019
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Epidermal growth factor receptor (EGFR) and activin A are both overexpressed in oral cavity squamous cell carcinoma (OSCC). We evaluated their clinical correlation and activin A-mediated EGFR regulation in this study. Overexpression of both transcripts/proteins indicated a poorer prognosis in OSCC patients. Knockdown of endogenous INHBA repressed the expression of EGFR and inhibited activin A-mediated canonical Smads, noncanonical phosphorylation of AKT (ser473) (p-AKT ser473) and SP1. Inhibition of PI3K signaling via its inhibitor attenuated p-AKT ser473 and in turn reduced SP1 and EGFR expression in the presence of recombinant activin A (rActivin A) in OSCC cells, as revealed via a luciferase assay and western blotting. However, canonical Smad signaling repressed the EGFR promoter, as revealed by a luciferase assay. The transcription factor SP1, its coactivator CBP/p300, and Smad proteins were recruited to the EGFR proximal promoter following rActivin A treatment, as revealed by chromatin immunoprecipitation (ChIP). Smad2/3/4 dramatically outcompeted SP1 binding to the EGFR proximal promoter following mithramycin A treatment. Activin A activates the PI3K and Smad pathways to compete for binding to overlapping SP1 consensus sequences on the EGFR proximal promoter. Nevertheless, canonical p-Smad2 was largely repressed in OSCC tumor tissues, suggesting that the activin A-mediated noncanonical pathway is essential for the carcinogenesis of OSCC.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2045-2322eISSN: 2045-2322DOI: 10.1038/s41598-019-41396-7Titel-ID: cdi_doaj_primary_oai_doaj_org_article_b8fec2df7ecf4364b817c043c7c50159
- Format
- –
- Schlagworte
- 1-Phosphatidylinositol 3-kinase, Activin, Activins - metabolism, Adult, Aged, Aged, 80 and over, AKT protein, Carcinogenesis, Carcinoma, Squamous Cell - genetics, Cell Movement, Chromatin, Epidermal growth factor, Epidermal growth factor receptors, ErbB Receptors - genetics, ErbB Receptors - metabolism, Event-related potentials, Female, Humans, Immunoprecipitation, Male, Middle Aged, Mouth Neoplasms - genetics, Oral cancer, Oral cavity, Oral squamous cell carcinoma, p300-CBP Transcription Factors - metabolism, Phosphatidylinositol 3-Kinases - metabolism, Phosphorylation, Promoter Regions, Genetic, Proto-Oncogene Proteins c-akt - metabolism, RNA Interference, Signal Transduction, Smad protein, Smad2 protein, Smad2 Protein - metabolism, Sp1 protein, Sp1 Transcription Factor - metabolism, Squamous cell carcinoma, Western blotting, Young Adult