Identification of a BRAF/PA28?/MEK1 signaling axis and its role in epithelial-mesenchymal transition in oral submucous fibrosis.

Oral submucous fibrosis (OSF) is a chronic and insidious oral potentially malignant disorder associated with a 4-17% risk of oral squamous cell carcinoma (OSCC). Our previous study found that proteasomal activator 28?gamma (PA28?) is frequently overexpressed in oral squamous cell carcinoma and negatively correlated with poor patient prognosis. However, the ...
role of PA28? in the occurrence and development of OSF remains unclear. Here, we screened PA28?-related genes and investigated their function in OSF. We demonstrated that the expression of PA28? was positively associated with MEK1 and gradually elevated from normal to progressive stages of OSF tissue. Arecoline, a pathogenic component of OSF, could upregulate the protein levels of PA28? and phosphorylated MEK1 and contribute to epithelial to mesenchymal transition (EMT) in epithelial cells. Notably, PA28? could interact with MEK1 and upregulate its phosphorylation level. Furthermore, arecoline upregulated BRAF, which can interact with PA28? and upregulate its protein level. Additionally, BRAF, PA28?, and MEK1 could form protein complexes and then enhance the MEK1/ERK signaling pathways. The concrete mechanism of the protein stability of PA28? is that BRAF mediates its degradation by inhibiting its ubiquitination. These findings underscore the instrumental role of PA28? in the BRAF/MEK1 pathway and enhanced EMT through MEK1/ERK activation in OSF.
Mesh Terms:
Arecoline, Autoantigens, Carcinoma, Squamous Cell, Epithelial-Mesenchymal Transition, Head and Neck Neoplasms, Humans, MAP Kinase Kinase 1, Mouth Neoplasms, Oral Submucous Fibrosis, Proteasome Endopeptidase Complex, Proto-Oncogene Proteins B-raf, Squamous Cell Carcinoma of Head and Neck
Cell Death Dis
Date: Aug. 12, 2022
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