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Tumor Suppressor Activity of CCAAT/Enhancer Binding Protein Is Epigenetically Down-regulated in Head and Neck Squamous Cell Carcinoma

Departments of ¹ Molecular Genetics, ² Molecular Virology, Immunology, and Medical Genetics, Division of Human Cancer Genetics, and ³ Pathology and The Comprehensive Cancer Center, Ohio State University, Columbus, Ohio; ⁴ University of Freiburg Medical Center, Freiburg, Germany; and ⁵ Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic Foundation and Taussig Cancer Center, Cleveland, Ohio

Requests for reprints: Christoph Plass, Ohio State University, Division of Human Cancer Genetics, Tzagournis Medical Research Facility 464A, 420 W. 12th Avenue, Columbus, OH 43210. Phone: 614-292-6505; Fax: 614-688-4761; E-mail: Christoph.Plass{at}osumc.edu.

Tumor suppressor CCAAT enhancer binding protein (C/EBP) is a transcription factor involved in cell cycle control and cellular differentiation. In a recent study, microarray expression profiling on head and neck squamous cell carcinoma (HNSCC) samples identified significant C/EBP down-regulation, correlating with poor prognosis. However, the mechanisms of C/EBP down-regulation remained elusive. C/EBP has been previously found to provide an antiproliferative role in lung cancer, and our laboratory showed that its down-regulation involves epigenetic mechanisms. This prompted us to investigate the involvement of epigenetics in down-regulating C/EBP in HNSCC. Here, we show that C/EBP is down-regulated in HNSCC by loss of heterozygosity and DNA methylation, but not by gene mutation. We found a consistently methylated upstream regulatory region (–1,399 bp to –1,253 bp in relation to the transcription start site) in 68% of the HNSCC tumor samples, and DNA demethylation using 5-aza-2'-deoxycytidine treatment was able to significantly restore C/EBP mRNA expression in the HNSCC cell lines we tested. In addition, C/EBP overexpression in a HNSCC cell line (SCC22B) revealed its ability to provide tumor suppressor activity in HNSCC in vitro and in vivo. In conclusion, we showed for the first time not only that C/EBP has tumor suppressor activity in HNSCC, but also that it is down-regulated by DNA promoter methylation. [Cancer Res 2007;67(10):4657–64]

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