Tumor suppressor activity of CCAAT/enhancer binding protein alpha is epigenetically down-regulated in head and neck squamous cell carcinoma.
Tumor suppressor CCAAT enhancer binding protein alpha (C/EBPalpha) 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/EBPalpha down-regulation, correlating with poor prognosis. However, the mechanisms of C/EBPalpha down-regulation remained elusive. C/EBPalpha 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/EBPalpha in HNSCC. Here, we show that C/EBPalpha 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/EBPalpha mRNA expression in the HNSCC cell lines we tested. In addition, C/EBPalpha 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/EBPalpha has tumor suppressor activity in HNSCC, but also that it is down-regulated by DNA promoter methylation.
Bennett
Kristi L
KL
Department of Molecular Genetics, The Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA.
Hackanson
Björn
B
Smith
Laura T
LT
Morrison
Carl D
CD
Lang
James C
JC
Schuller
David E
DE
Weber
Frank
F
Eng
Charis
C
Plass
Christoph
C
D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000096:biosynthesis / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D019175:DNA Methylation; D000077209:Decitabine; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D019656:Loss of Heterozygosity; D009362:Neoplasm Metastasis; D014162:Transfection
D022763:CCAAT-Enhancer-Binding Protein-alpha; D000077209:Decitabine; D001374:Azacitidine