Downregulation of HTATIP2 expression is associated with promoter methylation and poor prognosis in glioma
Downregulation of HTATIP2 expression is associated with promoter methylation and poor prognosis in glioma
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DOI：
10.1016/j.yexmp.2015.01.013
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发表时间：
2015-04-01
影响因子：
3.6
通讯作者：
Xu, Ruxiang
中科院分区：
文献类型：
--
作者：
Dong, Xingyu;Deng, Qingshan;Xu, Ruxiang
胶质瘤是一种侵袭性肿瘤，预后差。寻找准确的预后标志物和有效的治疗靶点是胶质瘤治疗的关键。HTATIP 2是一个新的肿瘤抑制基因，在许多癌症中经常被表观遗传机制沉默。然而，HTATIP2的表达及其在胶质瘤中的调节方式尚不清楚。因此，我们评估了HTATIP2表达的丢失是否发生在胶质瘤中，如果是这样，这种丢失的机制是什么。我们发现，与正常脑组织相比，HTATIP2表达在原发性胶质瘤中缺失或减少。体外实验表明，在U87和U251细胞系中，HTATIP2的表达可以通过5-氮杂-2 '脱氧胞苷处理而恢复。甲基特异性PCR检测结果表明，两种细胞系和60%的原发性胶质瘤细胞均携带异常甲基化的HTATIP 2等位基因，而正常脑组织中则没有。焦磷酸测序证实了这些结果，并显示在最小的启动子元件，其中包含四个Sp1结合位点在原发性胶质瘤，比在正常脑组织中的甲基化密度更高。最后，我们发现HTATIP2表达阳性的患者的总生存率显著高于HTATIP2表达缺失的患者。HTATIP2过表达抑制胶质瘤的增殖和生长。总之，本研究表明HTATIP2表达缺失是胶质瘤中的常见事件，并且与不良预后相关。启动子甲基化可能是一种潜在机制。ID（C）2015 Elsevier Inc. All rights reserved.
Glioma is an aggressive tumor with poor prognosis. Identification of precise prognostic marker and effective therapeutic target is important in the treatment of glioma. HTATIP2 is a novel tumor suppressor gene, which is frequently silenced by epigenetic mechanisms in many caners. However, the expression of HTATIP2 and how it is regulated in glioma are unknown. Hence, we assessed whether loss of HTATIP2 expression occurs in glioma, and, if so, what is the mechanism of such loss. We found that HTATIP2 expression was absent or diminished in primary gliomas compared with normal brain tissue. In vitro experiments showed that HTATIP2 expression could be restored via 5-aza-2'deoxycytidine treatment in U87 and U251 cell lines. Methyl-specific PCR indicated that the two cell lines and 60% primary gliomas carried aberrant methylated HTATIP2 alleles while normal brain tissue did not. Pyrosequencing confirmed these results and showed a higher density of methylation in the minimal promoter element, which contains four Sp1 binding sites in primary gliomas, than in normal brain tissue. Finally, we found that the overall survival was significantly higher in patients with positive HTATIP2 expression than those with loss of HTATIP2 expression. Overexpression of HTATIP2 inhibited glioma proliferation and growth in vitro. Taken together, the present study showed that loss of HTATIP2 expression was a frequent event in glioma and is associated with poor prognosis. Promoter methylation may be an underlying mechanism. ID (C) 2015 Elsevier Inc. All rights reserved.