CK2 abrogates the inhibitory effects of PRH/HHEX on prostate cancer cell migration and invasion and acts through PRH to control cell proliferation

Siddiqui, Yusra H.; Kershaw, Rachael M.; Humphreys, Elizabeth H.; Marcolino de Assis Junior, Eudmar; Chaudhri, Shalini; Jayaraman, Padma-Sheela; Gaston, Kevin

Abstract

PRH/HHEX (Proline Rich Homeodomain protein/Haematopoietically-Expressed Homeobox protein) is a transcription factor that controls cell proliferation, cell differentiation and cell migration. Our previous work has shown that in haematopoietic cells Protein Kinase CK2-dependent phosphorylation of PRH results in the inhibition of PRH DNA binding activity, increased cleavage of PRH by the proteasome, and the misregulation of PRH target genes. Here we show that PRH and hyperphosphorylated PRH are present in normal prostate epithelial cells, and that hyperphosphorylated PRH levels are elevated in benign prostatic hyperplasia, prostatic adenocarcinoma, and prostate cancer cell lines. A reduction in PRH protein levels increases the motility of normal prostate epithelial cells and conversely, PRH over-expression inhibits prostate cancer cell migration and blocks the ability of these cells to invade an extracellular matrix. We show that CK2 over-expression blocks the repression of prostate cancer cell migration and invasion by PRH. In addition, we show that PRH knockdown in normal immortalised prostate cells results in an increase in the population of cells capable of colony formation in Matrigel, as well as increased cell invasion and decreased E-cadherin expression. Inhibition of CK2 reduces PRH phosphorylation and reduces prostate cell proliferation but the effects of CK2 inhibition on cell proliferation are abrogated in PRH knockdown cells. These data suggest that the increased phosphorylation of PRH in prostate cancer cells increases both cell proliferation and tumour cell migration/invasion.

Citation

Siddiqui, Y. H., Kershaw, R. M., Humphreys, E. H., Marcolino de Assis Junior, E., Chaudhri, S., Jayaraman, P., & 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, https://doi.org/10.1038/oncsis.2016.82

• Journal Article Type: Article
• Acceptance Date: Jan 26, 2016
• Online Publication Date: Jan 30, 2017
• Publication Date: Jan 30, 2017
• Deposit Date: Sep 4, 2018
• Publicly Available Date: Sep 5, 2018
• Journal: Oncogenesis
• Electronic ISSN: 2157-9024
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 6
• DOI: https://doi.org/10.1038/oncsis.2016.82
• Keywords: HHEX, PRH, cell proliferation, cell migration, cell invasion, prostate cancer
• Public URL: https://nottingham-repository.worktribe.com/output/1037574