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

<div>Abstract<p>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 (<i>DUSP4/MKP-2</i>) that is hypermethylated in gliomas. In 83 astrocytic gliomas and 5 glioma cell lines examined, hypermethylation of the <i>MKP-2</i> promoter was found to occur relatively more frequently in diffuse or anaplastic astrocytomas and secondary glioblastomas relative to primary glioblastomas. <i>MKP-2</i> hypermethylation was associated with mutations in <i>TP53</i> and <i>IDH1</i>, exclusive of <i>EGFR</i> amplification, and with prolonged survival of patients with primary glioblastoma. Expression analysis established that promoter hypermethylation correlated with reduced expression of <i>MKP-2</i> mRNA and protein. Consistent with a regulatory role, reversing promoter hypermethylation by treating cells with 5-aza-2′-deoxycytidine increased <i>MKP-2</i> mRNA levels. Furthermore, we found that glioblastoma cell growth was inhibited by overexpression of exogenous <i>MKP-2</i>. Our findings reveal <i>MKP-2</i> as a common epigenetically silenced gene in glioma, the inactivation of which may play a significant role in glioma development. Cancer Res; 70(4); 1689–99</p></div>