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

Department of Neuropathology, University of Bonn, D-53105 Bonn, Germany.
Cancer Research (Impact Factor: 9.33). 02/2010; 70(4):1689-99. DOI: 10.1158/0008-5472.CAN-09-3218
Source: PubMed


Critical tumor suppression pathways in brain tumors have yet to be fully defined. Along with mutational analyses, genome-wide epigenetic investigations may reveal novel suppressor elements. Using differential methylation hybridization, we identified a CpG-rich region of the promoter of the dual-specificity mitogen-activated protein kinase phosphatase-2 gene (DUSP4/MKP-2) that is hypermethylated in gliomas. In 83 astrocytic gliomas and 5 glioma cell lines examined, hypermethylation of the MKP-2 promoter was found to occur relatively more frequently in diffuse or anaplastic astrocytomas and secondary glioblastomas relative to primary glioblastomas. MKP-2 hypermethylation was associated with mutations in TP53 and IDH1, exclusive of EGFR amplification, and with prolonged survival of patients with primary glioblastoma. Expression analysis established that promoter hypermethylation correlated with reduced expression of MKP-2 mRNA and protein. Consistent with a regulatory role, reversing promoter hypermethylation by treating cells with 5-aza-2'-deoxycytidine increased MKP-2 mRNA levels. Furthermore, we found that glioblastoma cell growth was inhibited by overexpression of exogenous MKP-2. Our findings reveal MKP-2 as a common epigenetically silenced gene in glioma, the inactivation of which may play a significant role in glioma development.

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Available from: Elmar Endl, Mar 07, 2014
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    • "Of interest, the DUSP4 gene product dephosphorylates and thereby inactivates MAPKs, which are involved in regulation of growth and proliferation. Further, by blocking the MAPK cascade, DUSP4 could act as a candidate tumor suppressor gene [26]. "
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    • "DUSP-4 also is functional as a tumor growth suppressor. Waha et al. (2010) found that overexpression of DUSP-4 in GBM cell lines led to a significant reduction in cellular proliferation and colony formation. DUSP-4 was also implicated in the negative feedback loop for MAPK desensitization by the binding of transcription factors to the DUSP-4 promoter, which prevented its methylation. "
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    • "For example, deletion or abnormal expression of DUSP4 has been demonstrated in breast cancer using fluorescence in situ hybridization [20] [21] [23]. The role of DUSP4 as a tumor suppressor is supported by the fact that overexpression of exogenous DUSP4 inhibits the growth of glioma cells [23]. Since consensus has not been reached on the role of DUSP4 in breast cancer, we studied the expression of DUSP4 in different breast cancer cell lines. "
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