The molecular causes leading to secondary liver
malignancies are unknown. Here we report regulation of major hepatic nuclear factors in human colorectal liver
metastases and primary
colonic cancer. Notably, the genes coding for HNF6, HNF1beta, and
C/EBPgamma were selectively regulated in liver
metastases. We therefore studied
protein expression of regulated
transcription factors and found unacetylated HNF6 to be a hallmark of colorectal liver
metastases. For its known interaction with HNF6, we investigated expression of FOXA2, which we found to be specifically induced in colorectal liver
metastases. By electromobility shift assay, we examined
DNA binding of disease regulated
transcription factors. Essentially, no HNF6
DNA binding was observed. We also searched for sequence variations in the
DNA binding domains of HNF6, but did not identify any mutation. Furthermore, we probed for expression of 28 genes targeted by HNF6. Mostly transcript expression was repressed except for
tumor growth. In conclusion, we show HNF6
protein expression to be driven by the hepatic environment. Its expression is not observed in healthy colon or primary
colonic cancer. HNF6
DNA binding is selectively abrogated through lack of post-translational modification and interaction with FOXA2. Targeting of FOXA2 and HNF6 may therefore enable mechanism-based
therapy for colorectal liver
metastases.