Identification of Global DNA Methylation Signatures in Glioblastoma-Derived Cancer Stem Cells.
Identification of Global DNA Methylation Signatures in Glioblastoma-Derived Cancer Stem Cells.
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DOI：
10.1016/j.jgg.2015.06.003
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发表时间：
2015-07-20
期刊：
影响因子：
--
通讯作者：
Shi H
中科院分区：
文献类型：
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作者：
Lee EJ;Rath P;Liu J;Ryu D;Pei L;Noonepalle SK;Shull AY;Feng Q;Litofsky NS;Miller DC;Anthony DC;Kirk MD;Laterra J;Deng L;Xin HB;Wang X;Choi JH;Shi H
胶质母细胞瘤（GBM）是成人中最常见和最具侵袭性的原发性脑肿瘤。有效地增殖肿瘤并抵抗细胞毒性疗法的干细胞样肿瘤细胞的小群体的存在是导致肿瘤细胞的弹性行为和不良预后的一种提出的机制。在这项研究中，我们对GBM衍生的癌症干细胞（GSC）中的DNA甲基化景观进行了深入分析。将原发性肿瘤和来源于这些肿瘤的GSC系与正常对照（神经干细胞（NSC）系和正常脑组织）进行平行比较，鉴定了高甲基化和低甲基化基因组，其分别以对照、原发性GBM和它们的对应GSC系的顺序显示甲基化水平增加或降低的趋势。有趣的是，在包括MGMT、AJAP1和PTPRN2的基因亚组中观察到同时发生的启动子高甲基化和基因体低甲基化。这些独特的DNA甲基化特征也在原发性GBM来源的异种移植肿瘤中发现，表明它们不是组织培养相关的表观遗传变化。GSC特异性表观遗传标记与基因表达分析的整合进一步鉴定了在GBM中经常下调的候选肿瘤抑制基因，如SPINT 2、NEFM和PENK。在体外，SPINT 2的强制再表达降低了胶质瘤细胞的增殖能力、非锚定依赖性生长、细胞运动性和肿瘤球形成。本研究的结果表明，GSC具有独特的表观遗传特征，可能在GBM的发病机制中发挥重要作用。
Glioblastoma (GBM) is the most common and most aggressive primary brain tumor in adults. The existence of a small population of stem-like tumor cells that efficiently propagate tumors and resist cytotoxic therapy is one proposed mechanism leading to the resilient behavior of tumor cells and poor prognosis. In this study, we performed an in-depth analysis of the DNA methylation landscape in GBM-derived cancer stem cells (GSCs). Parallel comparisons of primary tumors and GSC lines derived from these tumors with normal controls (a neural stem cell (NSC) line and normal brain tissue) identified groups of hyper- and hypomethylated genes that display a trend of either increasing or decreasing methylation levels in the order of controls, primary GBMs, and their counterpart GSC lines, respectively. Interestingly, concurrent promoter hypermethylation and gene body hypomethylation were observed in a subset of genes including MGMT, AJAP1 and PTPRN2. These unique DNA methylation signatures were also found in primary GBM-derived xenograft tumors indicating that they are not tissue culture-related epigenetic changes. Integration of GSC-specific epigenetic signatures with gene expression analysis further identified candidate tumor suppressor genes that are frequently down regulated in GBMs such as SPINT2, NEFM and PENK. Forced re-expression of SPINT2 reduced glioma cell proliferative capacity, anchorage independent growth, cell motility, and tumor sphere formation in vitro. The results from this study demonstrate that GSCs possess unique epigenetic signatures that may play important roles in the pathogenesis of GBM.