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

Kershaw, Rachel M.; Siddiqui, Yusra H.; Roberts, Dan; Jayaraman, P.-S.; Gaston, Kevin

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.

Citation

Kershaw, R. M., Siddiqui, Y. H., Roberts, D., Jayaraman, P.-S., & Gaston, K. (2014). PRH/HHex inhibits the migration of breast and prostate epithelial cells through direct transcriptional regulation of Endoglin. Oncogene, 33, 5592-5600. https://doi.org/10.1038/onc.2013.496

• Journal Article Type: Article
• Acceptance Date: Oct 11, 2013
• Online Publication Date: Nov 18, 2013
• Publication Date: Dec 4, 2014
• Deposit Date: Sep 4, 2018
• Publicly Available Date: Mar 6, 2019
• Journal: Oncogene
• Print ISSN: 0950-9232
• Electronic ISSN: 1476-5594
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 33
• Pages: 5592-5600
• DOI: https://doi.org/10.1038/onc.2013.496
• Keywords: HHex, PRH, cell migration, invasion, breast cancer, prostate cancer
• Public URL: https://nottingham-repository.worktribe.com/output/1037597
• Publisher URL: https://www.nature.com/articles/onc2013496
• Contract Date: Sep 4, 2018