HNF1α and CDX2 transcriptional factors bind to cadherin-17 (CDH17) gene promoter and modulate its expression in hepatocellular carcinoma.
Cadherin-17 (CDH17) belongs to the cell adhesion cadherin family with a prominent role in tumorigenesis. It is highly expressed in human hepatocellular carcinoma (HCC) and is proposed to be a biomarker and therapeutic molecule for liver malignancy. The present study aims to identify the transcription factors which interact and regulate CDH17 promoter activity that might contribute to the up-regulation of CDH17 gene in human HCC. A 1-kb upstream sequence of CDH17 gene was cloned and the promoter activity was studied by luciferase reporter assay. By bioinformatics analysis, deletion and mutation assays, and chromatin immunoprecipitation studies, we identified hepatic nuclear factor 1α (HNF1α) and caudal-related homeobox 2 (CDX2) binding sites at the proximal promoter region which modulate the CDH17 promoter activities in two HCC cell lines (Hep3B and MHCC97L). A consistent down-regulation of CDH17 and the two transcriptional activators (HNF1α and CDX2) expression was found in the liver of mouse during development, as well as in human liver cancer cells with less metastatic potential. Suppression of HNF1α and CDX2 expression by small interfering RNA (siRNA) significantly down-regulated expressions of CDH17 and its downstream target cyclin D1 and the viability of HCC cells in vitro. In summary, we identified the minimal promoter region of CDH17 that is regulated by HNF1α and CDX2 transcriptional factors. The present findings enhance our understanding on the regulatory mechanisms of CDH17 oncogene in HCC, and may shed new insights into targeting CDH17 expression as potential therapeutic intervention for cancer treatment.
Zhu
Rui
R
Department of Surgery and Center for Cancer Research, The University of Hong Kong, Pokfulam, Hong Kong, China.
Wong
Kwong-Fai
KF
Lee
Nikki P Y
NP
Lee
Kai-Fai
KF
Luk
John M C
JM
D000818:Animals; D000071616:CDX2 Transcription Factor; D015820:Cadherins / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000502:physiology*; D018398:Homeodomain Proteins / Q000502:physiology*; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology; D014407:Tumor Cells, Cultured
C490584:CDH17 protein, human; D000071616:CDX2 Transcription Factor; D015820:Cadherins; D051538:Hepatocyte Nuclear Factor 1-alpha; D018398:Homeodomain Proteins; D015534:Trans-Activators; D014157:Transcription Factors