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Dual-Specificity Phosphatase DUSP6 Has Tumor-Promoting Properties In Oncogene (2011) 30, 3813–3820 & 2011 Macmillan Publishers Limited All rights reserved 0950-9232/11 www.nature.com/onc SHORT COMMUNICATION Dual-specificity phosphatase DUSP6 has tumor-promoting properties in human glioblastomas S Messina1,2, L Frati1, C Leonetti3, C Zuchegna4,5, E Di Zazzo4, A Calogero6 and A Porcellini5 1Department of Pathology, IRCCS Neuromed, Pozzilli, Italy; 2Department of Health and Motor Sciences, University of Cassino, Cassino, Italy; 3Department of Experimental Chemotherapy, Regina Elena Cancer Institute, Rome, Italy; 4Department of Health Sciences, University of Campobasso, Campobasso, Italy; 5Department of Structural and Functional Biology, Federico II University of Naples, Naples, Italy and 6Department of Medical and Surgical Sciences and Biotecnology, Sapienza University of Rome, Rome, Italy Dual-specificity phosphatase 6 (DUSP6, mitogen-acti- signaling by dephosphorylating components of the vated protein kinase (MAPK) phosphatase 3 or PYST1) MAPK cascade. DUSPs are typically negative feedback dephosphorylates phosphotyrosine and phosphothreonine regulators of MAPK activity that become transcription- residues on extracellular signal-regulated kinase (ERK1/ ally induced after stress or mitogenic stimulation; this 2; MAPK1/2) to inactivate the ERK1/2 kinase. DUSP6 is leads to early production of proteins that inactivate a critical regulator of the ERK signaling cascade and has MAPKs within 20–40 min (Owens and Keyse, 2007). been implicated as a tumor suppressor. We report here Importantly, some DUSPs may provide biomarkers of experimental evidences that DUSP6 is transcriptionally therapeutic responsiveness and patient outcome in upregulated in primary and long-term cultures of human specific cancers, as well as DUSP1 and DUSP2 in glioblastoma, as assayed by northern hybridization and different type of cancers (reviewed in Patterson et al., real-time quantitative PCR, producing constitutive high 2009). level of protein expression. Functional assays were performed DUSP6 is a cytoplasmic member of this family that with adenovirus-mediated expression of DUSP6 in glio- has been implicated in the development of cancer. blastoma cultures. Protein overexpression inhibits growth by Pancreatic cancer cells progress towards a more inducing G1-phase delay and increased mitogenic/anchorage aggressive and invasive phenotype, following loss of dependence and clonogenic potential in vitro. Changes in cell DUSP6 expression (Furukawa et al., 2003, 2005). morphology were associated with an increased tumor growth Overexpression of DUSP6 in estrogen receptor-positive in vivo. Chemoresistance is a major cause of treatment failure breast cancer cells confers resistance to the growth and poor outcome in human glioblastomas. Importantly, inhibitory effects of tamoxifen (Cui et al., 2006) and its DUSP6 overexpression increased resistance to cisplatin- expression is strongly upregulated in HER2-positive mediated cell death in vitro and in vivo.Antisense-mediated breast tumors (Lucci et al., 2010). Moreover, DUSP6 depletion of DUSP6 acted in lowering the threshold to is part of a high-risk signature gene for non-small cell anticancer DNA-damaging drugs. We conclude that upregu- lung cancer (Chen et al., 2007), and its expression is lation of DUSP6 exerts a tumor-promoting role in human significantly correlated with high extracellular signal- glioblastomas exacerbating the malignant phenotype. regulated kinase (ERK) 1/2 activity in primary human Oncogene (2011) 30, 3813–3820; doi:10.1038/onc.2011.99; ovarian cancer cells (Chan et al.,2008).Remarkably,in published online 18 April 2011 human glioblastoma cells DUSP6 gene was induced upon platelet-derived growth factor (PDGF) stimulation Keywords: glioblastoma; dual-specificity phosphatase; (Tullai et al., 2004). Moreover, DUSP6 can be upregu- tumor promoting lated in specific cancers exhibiting aberrant receptor tyrosine kinase and Ras/Raf signaling, such as non-small cell lung cancer, potentially as a negative-feedback regulator of mitogenic signaling (Sato et al.,2006). Introduction Although the DUSP6 gene is a potential tumor- suppressor in some cancers (Furukawa et al., 2003, Dual-specificity phosphatases (DUSPs) negatively 2005; Okudela et al., 2009; Zhang et al., 2010), here, we regulate mitogen-activated protein kinase (MAPK) show that DUSP6 exerts tumor-promoting properties in glioblastoma cancers. Recently, some papers report that Correspondence: Dr S Messina, Department of Pathology, IRCCS upregulation of tumor suppressor genes might promote Neuromed, via Atinense, 18, Pozzilli, Isernia 86077, Italy. the malignant phenotype of cancer cells (Hong et al., E-mail: [email protected] or Professor A Porcellini, 2007). This split of personality was recently documented Department of Structural Biology, School of Biology, Federico II for PTEN and IDH1 genes in glioblastoma cancers University of Naples, Naples, Italy. E-mail: [email protected] (Li et al., 2008; Yan et al., 2009). Indeed, particular Received 8 September 2010; revised 3 February 2011; accepted 21 DUSPs may have contradicting roles in different tumor February 2011; published online 18 April 2011 types, such as DUSP1, that increased or decreased its DUSP6 regulation and function in glioblastoma cancer cells S Messina et al 3814 expression in different type of cancers, depending on the cultures of human glioblastoma, producing constitutive stage of carcinogenesis (reviewed in Patterson et al., high level of protein expression. Functional assays were 2009). performed with adenovirus-mediated expression of Glioblastoma multiforme is the most aggressive and DUSP6 in glioblastoma cultures. Protein overexpression frequent subtype of glioma, and shows very little inhibits growth by inducing G1-phase delay and response to chemotherapy (Maher et al., 2001). Re- inducing cell flattening that was associated with an cently, members of the DUSP family, such as DUSP26 increased tumor growth in vivo and inhibition of and DUSP4, have been involved in determining the epidermal growth factor (EGF)-detachment in vitro. malignant phenotype of glioblastomas (Tanuma et al., Finally, DUSP6 overexpression decreases tumor cell 2009; Waha et al., 2010). sensitivity to anticancer DNA-damaging cisplatin, We report here experimental evidence that DUSP6 is indicating that DUSP6 may function as a tumor transcriptionally upregulated in primary and long-term promoter in these cancers. Oncogene DUSP6 regulation and function in glioblastoma cancer cells S Messina et al 3815 Results and discussion major isoform in peripheral blood lymphocytes and, to a lesser extent, in normal human astrocytes. In human In order to establish differences in the expression of glioblastomas, in contrast, the shorter transcript was DUSP6 between normal and tumor cells, we first only induced by mitogenic stimulation. To determine analyzed the mRNA levels of DUSP6 by northern blot whether DUSP6 protein levels correlate with transcript and quantitative real-time PCR analysis in short- levels in human glioblastoma cultures, we performed passage cultures (FCN, MTR and MZC) (Calogero biochemical analysis by western blot. Immunoblots et al., 2004) and long-term human glioblastomas on cytosolic fraction showed negligible immuno- (U87MG and variants U87MGvEGFRIII, and kinase- reactivity of endogenous DUSP6 using commercial deficient U87MGDK) (Figure 1a). Comparing the antibodies, as reported previously (Mark et al., 2008). neoplastic cells with the normal counterpart (normal Next, we probed immunoblot membranes with a rabbit human astrocytes), we observed an increased expression polyclonal antibody (generated by Dr Lennartson) of DUSP6 (three- to sixfold) at baseline that increased against DUSP6, which recognizes a protein of 45 kDa upon mitogenic stimulation (Figure 1a, lower panel). (Figure 1c). Importantly, this antibody recognized Consistently, gene expression studies revealed DUSP6 constitutive high levels of endogenous DUSP6 as upregulation (mean fold changes: 3.14) in human multiple bands, probably due to various phosphoryla- astrocytic brain tumors compared with normal brain tion states (Dr Lennartson’s personal communication tissue (Petalidis et al., 2008). All cells were serum- and Figure 2d). starved overnight and stimulated with 100 ng/ml of EGF Functional assays were performed to focus on the for 3 h. Despite some fluctuation monitored, northern implication of DUSP6 overexpression in glioblastoma hybridization of non-neoplatic cells (unstimulated cul- cancers. In vitro assays were performed with replication- tures of murine pheochromocytoma PC12 cells, mouse deficient adenoviral vector harboring murine sense, fibroblasts NIH-3T3 and normal human astrocytes) antisense and C293S mutant DUSP6 (Muda et al., showed basal negligible mRNA levels and powerful 1996; Kim et al., 1996). The plasmid coding for murine induction of DUSP6 mRNA upon mitogenic stimula- DUSP6 includes a COOH-terminal myc-tag cloned in tion (Figure 1a, upper panel). As observed by Marchetti pAdTRK-CMV adenoviral shuttle in BglII-EcoRV et al. (2005), half-lives of DUSP6 mRNA was less than sites, which contains green fluorescent protein as a 1 h in heterologous expression systems; however, this is tracer (Porcellini and De Blasi, 2004). not the case for native DUSP6 in our system. Following Growth experiments (proliferation, thymidine incor- this line of evidence, we quantified DUSP6 mRNA by poration and cell-cycle analysis) were performed using real-time quantitative PCR in several cultures
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