The role of PRH/HHEX in TGF-β signaling and cancer cell-platelet interactions

Abstract

Dysregulated TGF-β signalling is implicated in supporting metastasis of cancer cells by promoting an epithelial-to-mesenchymal transition (EMT), with blood platelets proposed to represent a rich source of TGF-β for cancer cells that migrate into the vasculature. The proline-rich homeodomain protein (PRH) is a transcription factor that inhibits EMT and cell migration in part at least through modulation of TGF-β signalling. PRH levels are post-transcriptionally regulated via phosphorylation by the protein kinase CK2, which leads to subsequent proteasomal cleavage. PRH is hyper-phosphorylated in prostate cancer tissues and cell lines due to aberrant CK2 activity, potentially removing a restriction on pro-EMT TGF-β signalling. In the following MSc by Research project preliminary data is presented which suggests that TGF-β may promote a decrease in PRH abundance in ‘normal’ prostate PNT2-C2 cells, but by contrast may cause an increase in PRH levels in PC3 prostate cancer cells. Additionally, it was observed that in PC3 cells TGF-β may increase the abundance of phosphorylated PRH in a CK2-independent mechanism. It was found that platelet treatment did not recapitulate these findings, although preliminary observations suggest there may be changes at the mRNA level in the timeframe studied. Finally, it was observed that overexpression of PRH blocked TGF-β-mediated EMT changes, suggesting a possible target for prevention of pathological EMT in the body.

Date of Award	6 Nov 2018
Original language	English
Awarding Institution	The University of Bristol
Supervisor	Kevin Gaston (Supervisor)