Background: Activator protein 2 alpha (AP-2alpha) is involved in a variety of physiological processes. Increased AP-2alpha expression correlates with progression in various squamous cell carcinomas, and a recent publication found AP-2alpha to be overexpressed in approximately 70% of Head and Neck Squamous Cell Carcinoma (HNSCC) patient samples. It was found to repress transcription of the tumor suppressor gene C/CAAT Enhancer Binding Protein alpha (C/EBPalpha), and its binding site correlated with upstream methylation of the C/EBPalpha promoter. Therefore, we investigated the potential for AP-2alpha to target methylation to additional genes that would be relevant to HNSCC pathogenesis.
Principal findings: Stable downregulation of AP-2alpha stable by shRNA in HNSCC cell lines correlated with decreased methylation of its target genes' regulatory regions. Furthermore, methylation of MLH1 in HNSCC with and without AP-2alpha downregulation revealed a correlation with microsatellite instability (MSI). ChIP analysis was used to confirm binding of AP-2alpha and HDAC1/2 to the targets. The effects of HDAC inhibition was assessed using Trichostatin A in a HNSCC cell line, which revealed that AP-2alpha targets methylation through HDAC recruitment.
Conclusions: These findings are significant because they suggest AP-2alpha plays a role not only in epigenetic silencing, but also in genomic instability. This intensifies the potential level of regulation AP-2alpha has through transcriptional regulation. Furthermore, these findings have the potential to revolutionize the field of HNSCC therapy, and more generally the field of epigenetic therapy, by targeting a single gene that is involved in the malignant transformation via disrupting DNA repair and cell cycle control.