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

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 hyper-phosphorylated PRH are present in normal prostate epithelial cells, and that hyper-phosphorylated 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.

Gene Expression and Regulation in Mammalian Cells - Transcription From General Aspects

“…Both increased pPRH and increased PRH cytoplasmic localization are indicative of PRH inactivation and it is likely that this contributes to increased cell proliferation in these diseases. Interestingly, pPRH is less highly elevated in aggressive prostate adenocarcinomas and invasive breast carcinomas [35]. This could be due to decreased total PRH expression in these cancers.…”

“…In normal haematopoietic cells PRH protein is clearly discernable in distinct foci within the nucleus, co-localising with PML and translation factor eIF-4E [14,25], whereas in AML and CML PRH appears to be mislocalised to the cytoplasm [32]. Comparably, in thyroid cancer and breast cancer cells, PRH appears to be mislocalised from the nuclear compartment to the cytoplasm and often shows down-regulation in expression [33][34][35]. In breast and prostate cells loss of PRH activity results in increase cell proliferation and increased cell migration and invasion [35,36].…”

“…Comparably, in thyroid cancer and breast cancer cells, PRH appears to be mislocalised from the nuclear compartment to the cytoplasm and often shows down-regulation in expression [33][34][35]. In breast and prostate cells loss of PRH activity results in increase cell proliferation and increased cell migration and invasion [35,36]. Moreover, PRH over-expression in mouse mammary tumour cells inhibits tumour growth in vivo [36].…”

“…Pre-clinical studies have shown that pPRH is elevated in benign prostatic hyperplasias and in breast ductal carcinoma in situ compared to normal tissues [35,36]. PRH localization is also altered in prostate and breast tumours compared to normal tissue.…”

“…Many breast and prostate tumours for example do not need intervention and are currently over-treated by surgery because of a lack of biomarkers for prognosis. In pre-clinical studies the levels and localization of pPRH and PRH appear to be altered in breast and prostate tumours compared to controls [35,36]. However, additional studies with large numbers of patients will be required to determine whether pPRH and PRH or the pPRH/PRH ratio is a good prognostic indicator.…”