Epigenetic Downregulation of Mitogen-Activated Protein Kinase Phosphatase MKP-2 Relieves Its Growth Suppressive Activity in Glioma Cells
Epigenetic Downregulation of Mitogen-Activated Protein Kinase Phosphatase MKP-2 Relieves Its Growth Suppressive Activity in Glioma Cells
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DOI：
10.1158/0008-5472.can-09-3218
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发表时间：
2010-02-15
期刊：
影响因子：
11.2
通讯作者：
Waha, Andreas
中科院分区：
文献类型：
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作者：
Waha, Anke;Felsberg, Joerg;Waha, Andreas
脑肿瘤中的关键肿瘤抑制途径尚未完全确定。沿着突变分析，全基因组表观遗传学研究可能揭示新的抑制因子。使用差异甲基化杂交，我们确定了一个CpG丰富的区域的启动子的双特异性丝裂原活化蛋白激酶磷酸酶-2基因（DUSP4/MKP-2）是高甲基化的胶质瘤。在83个星形细胞胶质瘤和5个胶质瘤细胞系的检查，MKP-2启动子的高甲基化被发现相对更频繁地发生在弥漫性或间变性星形细胞瘤和继发性胶质母细胞瘤相对于原发性胶质母细胞瘤。MKP-2高甲基化与TP53和IDH1突变相关，不包括EGFR扩增，并与原发性胶质母细胞瘤患者的生存期延长相关。表达分析表明，启动子甲基化与MKP-2 mRNA和蛋白表达减少相关。与调节作用一致，通过用5-氮杂-2'-脱氧胞苷处理细胞来逆转启动子超甲基化增加了MKP-2 mRNA水平。此外，我们发现胶质母细胞瘤细胞的生长被抑制过表达的外源性MKP-2。我们的研究结果表明，MKP-2作为一个常见的表观遗传学沉默基因在胶质瘤中，其失活可能发挥重要作用，在胶质瘤的发展。Cancer Res; 70（4）; 1689 - 99. (C)2010年AACR。
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. Cancer Res; 70(4); 1689-99. (C) 2010 AACR.