ap-2α induces epigenetic silencing of tumor suppressive genes and microsatellite instability in head and neck squamous cell carcinomaap-2α诱发肿瘤抑制基因和微卫星不稳定的表观遗传沉默在头颈部鳞状细胞癌.pdf

AP-2a Induces Epigenetic Silencing of Tumor Suppressive Genes and Microsatellite Instability in Head and Neck Squamous Cell Carcinoma 1 1 1,2 Kristi L. Bennett , Todd Romigh , Charis Eng * 1 Genomic Medicine Institute, Lerner Research Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, United States of America, 2 Department of Genetics and Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America Abstract Background: Activator protein 2 alpha (AP-2a) is involved in a variety of physiological processes. Increased AP-2a expression correlates with progression in various squamous cell carcinomas, and a recent publication found AP-2a 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/EBPa), and its binding site correlated with upstream methylation of the C/EBPa promoter. Therefore, we investigated the potential for AP-2a to target methylation to additional genes that would be relevant to HNSCC pathogenesis. Principal Findings: Stable downregulation of AP-2a 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-2a downregulation revealed a correlation with microsatellite instability (MSI). ChIP analysis was used to confirm binding of AP- 2a 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-2a targets meth