AP-2α Induces Epigenetic Silencing of Tumor Suppressive Genes and Microsatellite Instability in Head and Neck Squamous Cell Carcinoma

BACKGROUND: Activator protein 2 alpha (AP-2α) is involved in a variety of physiological processes. Increased AP-2α expression correlates with progression in various squamous cell carcinomas, and a recent publication found AP-2α to be overexpressed in ∼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/EBPα), and its binding site correlated with upstream methylation of the C/EBPα promoter. Therefore, we investigated the potential for AP-2α to target methylation to additional genes that would be relevant to HNSCC pathogenesis. PRINCIPAL FINDINGS: Stable downregulation of AP-2α 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-2α downregulation revealed a correlation with microsatellite instability (MSI). ChIP analysis was used to confirm binding of AP-2α 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-2α targets methylation through HDAC recruitment. CONCLUSIONS: These findings are significant because they suggest AP-2α plays a role not only in epigenetic silencing, but also in genomic instability. This intensifies the potential level of regulation AP-2α 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.