Understanding the molecular mechanisms that control gene expression is central to understanding cell proliferation, cell migration and tumourigenesis and work in this area has laid the foundations for targeted cancer therapies. We are interested in the regulatory pathways that control the proliferation and migration of normal cells and the events that disrupt this control in tumourigenesis and metastasis. Our focus is the Proline Rich Homeodomain protein (PRH/Hhex), an oligomeric transcription factor that regulates cell proliferation and cell migration in multiple contexts. Changes in PRH localisation and activity are associated with several diseases including prostate cancer, breast cancer, thyroid cancer, liver cancer and some types of leukaemia. This suggests that in some cells PRH functions as a tumour suppressor protein.
Epithelial cells are held tightly together by cell adhesion proteins expressed on the cell surface. However, during Epithelial-Mesenchymal transition (EMT) these cells begin to express different cell adhesion proteins and they start to become more migratory. Transforming Growth Factor-beta (TGFbeta) is up-regulated in many tumours and this protein can induce EMT and increase cell migration. Our recent work has shown that TGFbeta induces EMT-like changes in normal immortalised prostate epithelial cells including changes in cell surface adhesion proteins and changes in cell migration. Our previous work showed that PRH directly regulates transcription of a TGFbeta co-receptor and that this is important for the regulation of prostate cell migration by PRH (Kershaw et al., 2014). In this project we will examine whether PRH counteracts the effects of TGFbeta on EMT and cell migration. The techniques that will be used include mammalian cell culture, western blotting, and cell migration assays.
(1) Siddiqui, Y.H., Kershaw, R.M., Humphreys, E. H., Marcolino de Assis Junior, E., Chaudhri, S., Jayaraman, P.-S., and Gaston, K. (2017) CK2 abrogates the inhibitory effects of PRH/HHEX on prostate cancer cell migration and invasion and acts through PRH to control cell proliferation. Oncogenesis, 6:e293
(2) Kershaw, R.M., Siddiqui, Y.H., Roberts, D., Jayaraman, P.S. and Gaston, K. (2014) PRH/Hhex inhibits the migration of breast and prostate epithelial cells through direct transcriptional regulation of Endoglin. Oncogene, 33:5592-600.
(3) Noy, P., Sawasdichai, A., Jayaraman, P.S. and Gaston, K. (2012) Protein kinase CK2 inactivates PRH/Hhex using multiple mechanisms to derepress VEGF signalling and promote cell survival. Nucleic Acids Research, 40: 9008-20.