| Popis: |
Tumor suppressor CCAAT enhancer binding protein α (C/EBPα) 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/EBPα down-regulation, correlating with poor prognosis. However, the mechanisms of C/EBPα down-regulation remained elusive. C/EBPα 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/EBPα in HNSCC. Here, we show that C/EBPα 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/EBPα mRNA expression in the HNSCC cell lines we tested. In addition, C/EBPα 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/EBPα has tumor suppressor activity in HNSCC, but also that it is down-regulated by DNA promoter methylation. [Cancer Res 2007;67(10):4657–64] |
