Coordinated activation of candidate proto-oncogenes and cancer testes antigens via promoter demethylation in head and neck cancer and lung cancer

• Published in: PloS one 2009-03, Vol.4 (3), p.e4961-e4961
• Main Authors: Smith, Ian M, Glazer, Chad A, Mithani, Suhail K, Ochs, Michael F, Sun, Wenyue, Bhan, Sheetal, Vostrov, Alexander, Abdullaev, Ziedulla, Lobanenkov, Victor, Gray, Andrew, Liu, Chunyan, Chang, Steven S, Ostrow, Kimberly L, Westra, William H, Begum, Shahnaz, Dhara, Mousumi, Califano, Joseph
• Format: Article
• Language: English
• Subjects: Aberration; Activation; Analysis; Animals; Antigens; Antigens, Neoplasm - genetics; Antigens, Neoplasm - metabolism; B cells; Base Sequence; Cancer; Cancer genetics; Cell Line, Tumor; Colorectal cancer; Demethylation; Deoxyribonucleic acid; DNA; DNA Methylation; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Epigenesis, Genetic; Epigenetic inheritance; Epigenetics; Footprinting; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene silencing; Genes; Genetic aspects; Genetic engineering; Genetics and Genomics/Bioinformatics; Genetics and Genomics/Cancer Genetics; Genetics and Genomics/Functional Genomics; Genetics and Genomics/Gene Discovery; Genetics and Genomics/Gene Expression; Genotype & phenotype; Head; Head & neck cancer; Head and neck cancer; Head and Neck Neoplasms - genetics; Head and Neck Neoplasms - metabolism; Homology; Humans; Infectious diseases; Lung cancer; Lung diseases; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lymphoma; Melanoma; Microarray Analysis; Molecular Sequence Data; Non-small cell lung cancer; Oncology/Head and Neck Cancers; Oncology/Lung Cancer; Otolaryngology; Pathogenesis; Pharmacology; Phylogeny; Promoter Regions, Genetic; Promoters; Proto-Oncogenes; Rodents; Solid tumors; Squamous cell carcinoma; Surgery; Transketolase - genetics; Transketolase - metabolism; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0004961

Epigenetic alterations have been implicated in the pathogenesis of solid tumors, however, proto-oncogenes activated by promoter demethylation have been sporadically reported. We used an integrative method to analyze expression in primary head and neck squamous cell carcinoma (HNSCC) and pharmacologically demethylated cell lines to identify aberrantly demethylated and expressed candidate proto-oncogenes and cancer testes antigens in HNSCC. We noted coordinated promoter demethylation and simultaneous transcriptional upregulation of proto-oncogene candidates with promoter homology, and phylogenetic footprinting of these promoters demonstrated potential recognition sites for the transcription factor BORIS. Aberrant BORIS expression correlated with upregulation of candidate proto-oncogenes in multiple human malignancies including primary non-small cell lung cancers and HNSCC, induced coordinated proto-oncogene specific promoter demethylation and expression in non-tumorigenic cells, and transformed NIH3T3 cells. Coordinated, epigenetic unmasking of multiple genes with growth promoting activity occurs in aerodigestive cancers, and BORIS is implicated in the coordinated promoter demethylation and reactivation of epigenetically silenced genes in human cancers.