A transcriptional profiling study of CCAAT/enhancer binding protein targets identifies hepatocyte nuclear factor 3β as a novel tumor suppressor in lung cancer

We showed previously that CCAAT/enhancer binding protein alpha(C/EBPalpha), a tissue-specific transcription factor, is a candidate tumor suppressor in lung cancer. In the present study, we have performed a transcriptional profiling study of C/EBPalpha target genes using an inducible cell line system. This study led to the identification of hepatocyte nuclear factor 3beta (HNF3beta), a transcription factor known to play a role in airway differentiation, as a downstream target of C/EBPalpha. We found down-regulation of HNF3beta expression in a large proportion of lung cancer cell lines examined and identified two novel mutants of HNF3beta, as well as hypermethylation of the HNF3beta promoter. We also developed a tetracycline-inducible cell line model to study the cellular consequences of HNF3beta expression. Conditional expression of HNF3beta led to significant growth reduction, proliferation arrest, apoptosis, and loss of clonogenic ability, suggesting additionally that HNF3beta is a novel tumor suppressor in lung cancer. This is the first study to show genetic abnormalities of lung-specific differentiation pathways in the development of lung cancer.