Epigenetic Downregulation of Mitogen-Activated Protein Kinase Phosphatase MKP-2 Relieves Its Growth Suppressive Activity in Glioma Cells

Waha, Anke; Felsberg, Jörg; Hartmann, Wolfgang; Knesebeck, Anna von dem; Mikeska, Thomas; Joos, Stefan; Wolter, Marietta; Koch, Arend; Yan, Pearlly S.; Endl, Elmar; Wiestler, Otmar D.; Reifenberger, Guido; Pietsch, Torsten; Waha, Andreas

doi:10.1158/0008-5472.can-09-3218

Cited by 67 publications

(68 citation statements)

References 44 publications

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“…Recently, members of the DUSPs family (DUSP26 and DUSP4) have been involved in determining the malignant phenotype of glioblastomas (Tanuma et al, 2009;Waha et al, 2010). In both papers, downregulation correlates with the invasive phenotype but, regretfully, the DUSP26 adhesive phenotypes were measured in heterologous expression systems.…”

Section: Dusp6 Regulation and Function In Glioblastoma Cancer Cells Smentioning

confidence: 99%

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Dual-specificity phosphatase DUSP6 has tumor-promoting properties in human glioblastomas

Messina

Frati

Leonetti³

et al. 2011

Oncogene

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Dual-specificity phosphatase 6 (DUSP6, mitogen-activated protein kinase (MAPK) phosphatase 3 or PYST1) dephosphorylates phosphotyrosine and phosphothreonine residues on extracellular signal-regulated kinase (ERK1/ 2; MAPK1/2) to inactivate the ERK1/2 kinase. DUSP6 is a critical regulator of the ERK signaling cascade and has been implicated as a tumor suppressor. We report here experimental evidences that DUSP6 is transcriptionally upregulated in primary and long-term cultures of human glioblastoma, as assayed by northern hybridization and real-time quantitative PCR, producing constitutive high level of protein expression. Functional assays were performed with adenovirus-mediated expression of DUSP6 in glioblastoma cultures. Protein overexpression inhibits growth by inducing G1-phase delay and increased mitogenic/anchorage dependence and clonogenic potential in vitro. Changes in cell morphology were associated with an increased tumor growth in vivo. Chemoresistance is a major cause of treatment failure and poor outcome in human glioblastomas. Importantly, DUSP6 overexpression increased resistance to cisplatinmediated cell death in vitro and in vivo. Antisense-mediated depletion of DUSP6 acted in lowering the threshold to anticancer DNA-damaging drugs. We conclude that upregulation of DUSP6 exerts a tumor-promoting role in human glioblastomas exacerbating the malignant phenotype.

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Section: Dusp6 Regulation and Function In Glioblastoma Cancer Cells Smentioning

confidence: 99%

“…Recently, members of the DUSP family, such as DUSP26 and DUSP4, have been involved in determining the malignant phenotype of glioblastomas (Tanuma et al, 2009;Waha et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Dual-specificity phosphatase DUSP6 has tumor-promoting properties in human glioblastomas

Messina

Frati

Leonetti³

et al. 2011

Oncogene

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“…DUSP4 encodes a member of the dual specificity protein phosphatase subfamily, which dephosphorylates both phosphothreonine and phosphotyrosine residues in MAPKs, inactivates MAPK signaling, and thereby inhibits cellular proliferation (19). DUSP4 was recently implicated as a novel tumor suppressor gene and its expression can be modulated by differential methylation in the promoter region (20). Patients with SRS and hypomethylation of ICR1 can also have methylation anomalies at other loci (21).…”

Section: Discussionmentioning

confidence: 99%

Post-receptor IGF1 insensitivity restricted to the MAPK pathway in a Silver–Russell syndrome patient with hypomethylation at the imprinting control region on chromosome 11

Montenegro

Leal²,

Coutinho³

et al. 2012

European Journal of Endocrinology

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Background: Hypomethylation of the paternal imprinting center region 1 (ICR1) is the most frequent molecular cause of Silver-Russell syndrome (SRS). Clinical evidence suggests that patients with this epimutation have mild IGF1 insensitivity. Objective: To assess in vitro IGF1 action in fibroblast culture from a patient with SRS and IGF1 insensitivity. Methods: Fibroblast cultures from one patient with SRS due to ICR1 demethylation and controls were established. The SRS patient has severe growth failure, elevated IGF1 level, and poor growth rate during human recombinant GH treatment. IGF1 action was assessed by cell proliferation, AKT, and p42/44-MAPK phosphorylation. Gene expression was determined by real-time PCR. Results: Despite normal IGF1R sequence and expression, fibroblast proliferation induced by IGF1 was 50% lower in SRS fibroblasts in comparison with controls. IGF1 and insulin promoted a p42/44-MAPK activation in SRS fibroblasts 40 and 36%, respectively, lower than that in control fibroblasts. On the other hand, p42/44-MAPK activation induced by EGF stimulation was only slightly reduced (75% in SRS fibroblasts in comparison with control), suggesting a general impairment in MAPK pathway with a greater impairment of the stimulation induced by insulin and IGF1 than by EGF. A PCR array analysis disclosed a defect in MAPK pathway characterized by an increase in DUSP4 and MEF2C gene expressions in patient fibroblasts. Conclusion: A post-receptor IGF1 insensitivity was characterized in one patient with SRS and ICR1 hypomethylation. Although based on one unique severely affected patient, these results raise an intriguing mechanism to explain the postnatal growth impairment observed in SRS patients that needs confirmation in larger cohorts.

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“…We have previously established DUSP4/MKP2 as a frequent target for epigenetic silencing that shows a similar prevalence for low-grade diffuse astrocytomas, anaplastic astrocytomas and secondary glioblastomas. 13 So far, there is only little information about epigenetic modification of SGNE1/7B2 in human tumors. In a previous report we described hypermethylation of SGNE1/7B2 in medulloblastomas, the most frequent malignant brain tumor of childhood.…”

Section: Discussionmentioning

confidence: 99%

“…Increasing numbers of genes associated with epigenetic alterations have been identified in human gliomas e.g., MGMT, CDKN2A, CDKN2B, p14ARF, CTMP, EMP3, SLC5A8, HIC-1, PCDH-c-A11, BEX1, BEX2, LATS1, LATS2, RUNX3, TES, DUSP4 and CASPR2. [5][6][7][8][9][10][11][12][13][14][15][16] The identification of new genes functionally involved in tumor development and progression may help to find alternative approaches for diagnostic and therapeutic evaluation. …”

mentioning

confidence: 99%

Frequent epigenetic inactivation of the chaperone SGNE1/7B2 in human gliomas

Waha

Felsberg

Hartmann

et al. 2011

Intl Journal of Cancer

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In a genome-wide screen using DMH (differential methylation hybridization) we have identified a CpG island within the 5 0 region and untranslated first exon of the secretory granule neuroendocrine protein 1 gene (SGNE1/7B2) that showed hypermethylation in low-and high-grade astrocytomas compared to normal brain tissue. Pyrosequencing was performed to confirm the methylation status of this CpG island in 89 astrocytic gliomas of different malignancy grades and six glioma cell lines. Hypermethylation of SGNE1/7B2 was significantly more frequent in diffuse low-grade astrocytomas as well as secondary glioblastomas and anaplastic astrocytomas as compared to primary glioblastomas. mRNA expression analysis by real-time RT-PCR indicates that SGNE1/7B2 expression is downregulated in astrocytic gliomas compared to white matter samples. Treatment of glioma cells with the demethylating agent 5-aza-2 0 -deoxycytidine restores the transcription of SGNE1/7B2. Overexpression of SGNE1/7B2 in T98G, A172 and U373MG glioblastoma cells significantly suppressed focus formation and led to a significant increase in apoptotic cells as determined by flow cytometric analysis in T98G cells. In summary, we have identified SGNE1/7B2 as a novel target silenced by DNA methylation in astrocytic gliomas. The high incidence of this alteration and the significant effects of SGNE1/7B2 on the growth and apoptosis of glioblastoma cells provide a first proof for a functional implication of SGNE1/7B2 inactivation in the molecular pathology of gliomas.Glioblastomas are the most frequent and most malignant tumors arising in the brain with a peak incidence between 45 and 70 years. 1 Despite recent therapeutic advances, these tumors respond poorly to radiation therapy and most forms of chemotherapy and retain a dismal prognosis with most patients dying within 1 year after diagnosis. Glioblastomas WHO Grade IV may develop through malignant progression from diffuse astrocytomas WHO Grade II or anaplastic astrocytomas WHO Grade III (secondary glioblastoma), but more frequently, de novo without evidence of a less malignant precursor lesion (primary glioblastoma). Several comprehensive profiling studies have uncovered a high incidence of genetic and epigenetic alterations in glioblastomas, some of which are specific for certain clinical glioblastoma subtypes. Primary glioblastomas frequently show loss of heterozygosity on chromosome 10q (70% of cases), EGFR amplification (36%), p16 (INK4a) deletion (31%) and PTEN mutations (25%). 2 Secondary glioblastomas as well as their lower grade precursor lesions exhibit frequent mutations of the TP53 and IDH1 genes. 2,3 Loss of genetic material from chromosome 10q25-qter is associated with both primary and secondary glioblastomas. 2 Promoter CpG island hypermethylation generally results in transcriptional silencing of associated genes and is crucial for the development of cancer. 4 Epigenetic alterations within promoter regions effect the binding affinity of transcription factors by interfering with transcription initiatio...

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Epigenetic Downregulation of Mitogen-Activated Protein Kinase Phosphatase MKP-2 Relieves Its Growth Suppressive Activity in Glioma Cells

Cited by 67 publications

References 44 publications

Dual-specificity phosphatase DUSP6 has tumor-promoting properties in human glioblastomas

Dual-specificity phosphatase DUSP6 has tumor-promoting properties in human glioblastomas

Post-receptor IGF1 insensitivity restricted to the MAPK pathway in a Silver–Russell syndrome patient with hypomethylation at the imprinting control region on chromosome 11

Frequent epigenetic inactivation of the chaperone SGNE1/7B2 in human gliomas

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