Dual‐specificity phosphatase 1 and serum/glucocorticoid‐regulated kinase are downregulated in prostate cancer

Abstract

Inactivation of tumor suppressor genes through deletion, mutation and epigenetic silencing has been shown to occur in cancer. In our study, we combined DNA demethylation and histone deacetylation inhibition treatments with suppression subtraction hybridization (SSH) and cDNA microarrays to identify potentially epigenetically downregulated genes in PC-3 prostate cancer cell line. We found 11 genes whose expression was upregulated after relieving epigenetic regulation. Expression of 3 genes [dual-specificity phosphatase 1 (DUSP1), serum/glucocorticoid regulated kinase (SGK) and spermidine/spermine N1-acetyltransferase (SAT)] was subsequently studied in clinical sample material using real-time quantitative RT-PCR and immunohistochemistry. The DUSP1 and SGK mRNA expression was lower in hormone-refractory prostate carcinomas compared to benign prostate hyperplasia (BPH) or untreated prostate carcinomas. BPH, normal prostate and highgrade prostate intraepithelial neoplasia (PIN) expressed high levels of DUSP1 and SGK proteins. Ninety-two percent and 48% of the prostate carcinomas showed almost complete lack of DUSP1 and SGK proteins, respectively, indicating common downregulation of these genes. The genomic bisulphite sequencing did not reveal dense hypermethylation in the promoter regions of either DUSP1 or SGK. In conclusion, the data suggest that downregulation of DUSP1 and SGK is an early event and could be important in the tumorigenesis of prostate cancer. ' 2005 Wiley-Liss, Inc.

Gene expression profiling reveals molecular marker candidates of laryngeal squamous cell carcinoma

“…A low expression of DUSP1 has been observed in ovarian and prostate cancer (56,57). Moreover, in line with our study, Tomioka et al (58) observed a low expression of this gene in head and neck cancer.…”

Dual-Specificity Phosphatase 1 Ubiquitination in Extracellular Signal-Regulated Kinase–Mediated Control of Growth in Human Hepatocellular Carcinoma

“…Although much effort has focused on the molecular interactions modulating DUSP1 activity in mammalian cell lines, little is known about the role of DUSP1 in carcinogenesis. DUSP1 inactivation is frequent in prostate and urothelial tumors (16,17), and recent observations indicate that immunohistochemical positivity for DUSP1 in human HCC is associated with longer patients' survival (18). However, the interactions of DUSP1 with ERK and the SKP2/CKS1 ligase and the mechanisms responsible for DUSP1 inactivation in the liver and other tumors have not been analyzed to date.…”

Prostate Cancer Dephosphorylation Atlas

“…Accordingly, a later study showed DUSP1 mRNA expression to be lower in hormone-refractory prostate carcinomas than in benign prostate hyperplasia (BPH) or untreated prostate carcinomas. Higher DUSP1 protein levels were found in BPH, normal prostate and high-grade prostate intraepithelial neoplasia (Rauhala et al, 2005). Consistent with the low levels of DUSP1 in response to androgen ablation, DUSP1 mRNA was found to be upregulated upon androgen treatment of LNCaP cells (Arnoldussen et al, 2008) The androgen receptor (AR) has been identified as responsible for increased expression of DUSP1 (and several other DUSPs) upon interaction with testosterone.…”

“…Consistent with the low levels of DUSP1 in response to androgen ablation, DUSP1 mRNA was found to be upregulated upon androgen treatment of LNCaP cells (Arnoldussen et al, 2008) The androgen receptor (AR) has been identified as responsible for increased expression of DUSP1 (and several other DUSPs) upon interaction with testosterone. However, DUSP1 implication in prostate cancer is not yet fully resolved, since there have been reports showing that both high and low levels of DUSP1 may have an antiapoptotic effect, depending on which MAP kinase DUSP1 is targeting (Rauhala et al, 2005). Similarly, androgens protect LNCaP cells from 12-O-tetradecanoylphorbol-13-acetate-and thapsigargin-induced apoptosis via down-regulation of JNK activity through an increase in DUSP3 expression.…”