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Activin A regulates the epidermal growth factor receptor promoter by activating the PI3K/SP1 pathway in oral squamous cell carcinoma cells
- Source :
- Scientific Reports, Vol 9, Iss 1, Pp 1-14 (2019), Scientific Reports
- Publication Year :
- 2019
- Publisher :
- Springer Science and Business Media LLC, 2019.
-
Abstract
- 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.
- Subjects :
- Adult
Male
0301 basic medicine
Sp1 Transcription Factor
Science
Smad2 Protein
SMAD
medicine.disease_cause
Article
Phosphatidylinositol 3-Kinases
Young Adult
03 medical and health sciences
0302 clinical medicine
Cell Movement
Coactivator
medicine
Humans
p300-CBP Transcription Factors
Epidermal growth factor receptor
Phosphorylation
Promoter Regions, Genetic
Protein kinase B
PI3K/AKT/mTOR pathway
Aged
Aged, 80 and over
Sp1 transcription factor
Multidisciplinary
biology
Chemistry
Middle Aged
Activins
ErbB Receptors
stomatognathic diseases
030104 developmental biology
Carcinoma, Squamous Cell
Cancer research
biology.protein
Medicine
Female
Mouth Neoplasms
RNA Interference
Carcinogenesis
Proto-Oncogene Proteins c-akt
Chromatin immunoprecipitation
030217 neurology & neurosurgery
Signal Transduction
Subjects
Details
- ISSN :
- 20452322
- Volume :
- 9
- Database :
- OpenAIRE
- Journal :
- Scientific Reports
- Accession number :
- edsair.doi.dedup.....f675a02e35deb88b6866c885b5e8e8ee