Promoter hypermethylation-mediated down-regulation of LATS 1 and LATS2 in human astrocytoma
Promoter hypermethylation-mediated down-regulation of LATS 1 and LATS2 in human astrocytoma
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DOI：
10.1016/j.neures.2006.09.006
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发表时间：
2006-12-01
影响因子：
2.9
通讯作者：
Lu, Daru
中科院分区：
文献类型：
--
作者：
Jiang, Zheng;Li, Xingang;Lu, Daru
LATS1和LATS2是参与细胞周期调控的抑癌基因，但它们在人脑星形细胞瘤中的甲基化状态尚不清楚。甲基化特异性聚合酶链式反应发现88例星形细胞瘤中LATS1和LATS1基因启动子甲基化频率分别为63.66%(56/88)和71.5%(63/88)。而在10例正常脑组织中均未检测到LATS 1和LATS2启动子甲基化。随着星形细胞瘤的恶性发展，LATS1和LATS2的甲基化频率增加。实时定量聚合酶链式反应检测到LATS1和LATS2在不同病理级别的星形细胞瘤中的表达均显著降低(P<；0.05)。存在高甲基化的星形细胞瘤LATS1和LATS2的mRNA水平均显著低于未发生甲基化的星形细胞瘤(P<；0.01)。在U251和SHG-44细胞中检测到LATS1和LATS2的甲基化，5-氮杂脱氧胞苷可以恢复它们的表达，从而诱导细胞凋亡。我们的结果提示LATS1和LATS2基因在星形细胞瘤中的表达受该启动子高甲基化的影响。LATS-1和LATS-2基因的甲基化和mRNA表达可能为发展星形细胞瘤的诊断方法提供有用的线索。我们的结果还表明，LATS1和LATS2可能是星形细胞瘤治疗的有用靶点。(C)2006年爱思唯尔爱尔兰有限公司和日本神经科学学会。版权所有。
LATS1 and LATS2 are tumor suppressor genes implicated in the regulation of cell cycle, but their methylation statuses are still unknown in human astrocytoma. Here, we found that the promoter hypermethylation frequencies of LATS1 and LATS1 were 63.66% (56/88) and 71.5% (63/88) in 88 astrocytomas by methylation-specific PCR. But no methylation of LATS 1 and LATS2 promoter was detected in the 10 normal brain tissues. There was an increased methylation frequency of LATS1 and LATS2 with the malignant development of astrcytoma. By real-time PCR, the mRNA expression of LATS1 or LATS2 was detected significantly decreased in different pathological grade astrocytomas (P < 0.05). And the mRNA levels of LATS1 and LATS2 in astrocytomas with hypermethylation were both significantly (P < 0.01) lower than those without methylation. The methylation of LATS1 and LATS2 was detected in U251 and SHG-44 cell lines, and 5-aza-deoxycytidine could restore their expression to induce cell apoptosis. Our results suggested that LATS1 and LATS2 mRNA was down-regulated in astrocytoma by hypermethylation of the promoter. The methylation and mRNA expression of LATS 1 and LATS2 may provide useful clues to the development of the diagnostic assays for astrocytoma. Our results also suggested that LATS1 and LATS2 may be a useful target for astrocytoma therapy. (c) 2006 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.