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A Transcriptional Profiling Study of CCAAT/Enhancer Binding Protein Targets Identifies Hepatocyte Nuclear Factor 3ß as a Novel Tumor Suppressor in Lung Cancer

¹ Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston; ² Department of Dermatology, Brigham and Women’s Hospital, Boston; ³ Harvard Institutes of Medicine, Boston; ⁴ Center for Genome Research, Whitehead Institute/Massachusetts Institute of Technology, Cambridge, Massachusetts; ⁵ The Blood Center of SE Wisconsin, Milwaukee, Wisconsin

We showed previously that CCAAT/enhancer binding protein (C/EBP), 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/EBP target genes using an inducible cell line system. This study led to the identification of hepatocyte nuclear factor 3ß (HNF3ß), a transcription factor known to play a role in airway differentiation, as a downstream target of C/EBP. We found down-regulation of HNF3ß expression in a large proportion of lung cancer cell lines examined and identified two novel mutants of HNF3ß, as well as hypermethylation of the HNF3ß promoter. We also developed a tetracycline-inducible cell line model to study the cellular consequences of HNF3ß expression. Conditional expression of HNF3ß led to significant growth reduction, proliferation arrest, apoptosis, and loss of clonogenic ability, suggesting additionally that HNF3ß 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.

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