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PRH/HHex inhibits the migration of breast and prostate epithelial cells through direct transcriptional regulation of Endoglin

Oncogene volume 33, pages 5592–5600 (2014)Cite this article

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Abstract

PRH/HHex (proline-rich homeodomain protein) is a transcription factor that controls cell proliferation and cell differentiation in a variety of tissues. Aberrant subcellular localisation of PRH is associated with breast cancer and thyroid cancer. Further, in blast crisis chronic myeloid leukaemia, and a subset of acute myeloid leukaemias, PRH is aberrantly localised and its activity is downregulated. Here we show that PRH is involved in the regulation of cell migration and cancer cell invasion. We show for the first time that PRH is expressed in prostate cells and that a decrease in PRH protein levels increases the migration of normal prostate epithelial cells. We show that a decrease in PRH protein levels also increases the migration of normal breast epithelial cells. Conversely, PRH overexpression inhibits cell migration and cell invasion by PC3 and DU145 prostate cancer cells and MDA-MB-231 breast cancer cells. Previous work has shown that the transforming growth factor-β co-receptor Endoglin inhibits the migration of prostate and breast cancer cells. Here we show that PRH can bind to the Endoglin promoter in immortalised prostate and breast cells. PRH overexpression in these cells results in increased Endoglin protein expression, whereas PRH knockdown results in decreased Endoglin protein expression. Moreover, we demonstrate that Endoglin overexpression abrogates the increased migration shown by PRH knockdown cells. Our data suggest that PRH controls the migration of multiple epithelial cell lineages in part at least through the direct transcriptional regulation of Endoglin. We discuss these results in terms of the functions of PRH in normal cells and the mislocalisation of PRH seen in multiple cancer cell types.

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Acknowledgements

We are grateful to Professor Norman J Maitland (University of York) for PNT2-C2 cells and useful discussions, Professor Kate Nobes (University of Bristol) for access to live cell imaging, Professor Clare Isacke (Institute of Cancer Research) for the Endoglin expression vector, Professor Harry Mellor (University of Bristol) and Professor Roy Bicknell (University of Birmingham) for HUVECs and useful discussions, and Professor Carmelo Bernabeu (Centro de Investigaciones Biologicas, Madrid) for Endoglin-luciferase reporter constructs. We are grateful to Laura A V Rodriguez and Xin Yang for technical assistance. This work was funded by a Breast Cancer Campaign project grant to PSJ and KG. YHS is grateful to the University of Bristol for a PhD Scholarship and to the Charles Wallace Pakistan Trust for additional support. DR is grateful to the MRC for a PhD studentship.

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Author notes

  1. R M Kershaw and Y H Siddiqui: These authors contributed equally to this work.

  2. P-S Jayaraman and K Gaston: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Immunity and Infection, School of Medicine, University of Birmingham, Edgbaston, Birmingham, UK

    R M Kershaw, D Roberts & P-S Jayaraman

  2. School of Biochemistry, University Walk, University of Bristol, Bristol, UK

    Y H Siddiqui & K Gaston

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  1. R M Kershaw
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Correspondence to K Gaston.

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Kershaw, R., Siddiqui, Y., Roberts, D. et al. PRH/HHex inhibits the migration of breast and prostate epithelial cells through direct transcriptional regulation of Endoglin. Oncogene 33, 5592–5600 (2014). https://doi.org/10.1038/onc.2013.496

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