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FGFR4 overexpression in pancreatic cancer is mediated by an intronic enhancer activated by HNF1α

Oncogene volume 21, pages 8251–8261 (2002)Cite this article

Abstract

Fibroblast growth factor receptor 4 (FGFR4) is expressed in 50–70% of pancreatic carcinomas (PC) and a similar proportion of derived cell lines. Here we determine the sites of FGFR4 transcriptional initiation which show a pattern characteristic of genes with GC-rich, TATA-less promoters. We have examined the chromatin structure around the FGFR4 gene in a panel of expressing and non-expressing PC lines using the DNase I hypersensitive site assay. One region of hypersensitivity, located largely within intron 1, was found to be greatly extended in expressing cells. Subsequent functional analyses using reporter assays demonstrated that this region was able to act as a cell-specific enhancer, only showing significant activity in PC lines expressing endogenous FGFR4. Transcription factors able to bind to the enhancer were investigated using footprinting and mobility shift assays and two binding sites for Sp1 proteins and two sites able to bind hepatic nuclear factor 1 (HNF1) proteins were identified. Further reporter assays using constructs mutated in each binding site demonstrated that HNF1 binding was essential for enhancer activity in expressing cells, an observation that correlated with the increased abundance of HNF1α in these same cells as measured by Western blotting. Finally we show that exogenous expression of HNF1 factors in an FGFR4 non-expressing line led to an induction of enhancer activity in reporter assays and also activated expression of the endogenous gene. We conclude that HNF1α is a major determinant of FGFR4 expression in PC.

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Acknowledgements

We thank Moshe Yaniv and S Isshiki for useful discussions and the gift of reagents, and our colleagues Nick Lemoine and Jyrki Eloranta for critically reading the manuscript.

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Authors and Affiliations

  1. Cancer Research UK Molecular Oncology Unit, ICSM at Hammersmith Hospital, London, W12 0NN, UK

    Riyaz NH Shah, J Claire Ibbitt & Helen C Hurst

  2. Biomedicum Helsinki, POB 63, Haartmaninkatu 8, Helsinki, 00014, Finland

    Kari Alitalo

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  1. Riyaz NH Shah
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  2. J Claire Ibbitt
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  3. Kari Alitalo
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  4. Helen C Hurst
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Correspondence to Helen C Hurst.

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Shah, R., Ibbitt, J., Alitalo, K. et al. FGFR4 overexpression in pancreatic cancer is mediated by an intronic enhancer activated by HNF1α. Oncogene 21, 8251–8261 (2002). https://doi.org/10.1038/sj.onc.1206020

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