The transglutaminase 2 gene is aberrantly hypermethylated in glioma.
The transglutaminase 2 gene is aberrantly hypermethylated in glioma.
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DOI：
10.1007/s11060-010-0277-7
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发表时间：
2011-02
影响因子：
3.9
通讯作者：
Brown, Kevin D.
中科院分区：
文献类型：
--
作者：
Dyer, Lisa M.;Schooler, Kevin P.;Ai, Lingbao;Klop, Corinne;Qiu, Jingxin;Robertson, Keith D.;Brown, Kevin D.
转氨酶2（TG2）是一种广泛表达的蛋白质，其催化蛋白质/蛋白质交联。由于细胞外TG2交联细胞外基质的组分，因此认为TG2作为细胞侵袭的抑制剂起作用。我们最近发现，TG2基因（TGM2）是乳腺癌中表观遗传沉默的靶点，突出了驱动TG2表达减少的分子机制，这种异常分子事件可能有助于这种肿瘤类型的侵袭性。由于肿瘤侵袭性是脑肿瘤侵袭性的主要决定因素，我们试图确定TGM2是否是胶质瘤中表观遗传沉默的靶点。在一组培养的人脑胶质瘤细胞中对TGM2基因甲基化的分析表明，TGM2基因的5 ′侧翼区是高甲基化的，并且通过免疫印迹判断，该特征与TG2表达降低相关。此外，在存在全局DNA去甲基化剂5-氮杂-2 ′-脱氧胞苷和组蛋白去乙酰化酶抑制剂曲古抑菌素A的情况下培养胶质瘤细胞导致TG2在这些细胞系中重新表达。在原发性脑肿瘤中，我们观察到TGM2启动子通常是高甲基化的，并且该特征是癌症相关现象。使用计算机上可用的数据库，发现胶质瘤中的TG2表达变化很大，许多肿瘤显示该基因的过表达或低表达。由于TG 2的过表达通过NF κ B的异位激活导致对阿霉素的抗性，我们试图检测重组TG 2表达在用常用脑肿瘤治疗剂处理的胶质瘤细胞中的作用。我们观察到，除了多柔比星，TG2的表达驱动耐药CCNU;然而，TG2的表达并没有改变其他药物的敏感性测试。最后，TG2的催化无效突变体也能够支持胶质瘤细胞中的阿霉素抗性，表明转氨酶活性对于抗性表型不是必需的。
Transglutaminase 2 (TG2) is a ubiquitously expressed protein that catalyzes protein/protein crosslinking. Because extracellular TG2 crosslinks components of the extracellular matrix, TG2 is thought to function as a suppressor of cellular invasion. We have recently uncovered that the TG2 gene (TGM2) is a target for epigenetic silencing in breast cancer, highlighting a molecular mechanism that drives reduced TG2 expression, and this aberrant molecular event may contribute to invasiveness in this tumor type. Because tumor invasiveness is a primary determinant of brain tumor aggressiveness, we sought to determine if TGM2 is targeted for epigenetic silencing in glioma. Analysis of TGM2 gene methylation in a panel of cultured human glioma cells indicated that the 5′ flanking region of the TGM2 gene is hypermethylated and that this feature is associated with reduced TG2 expression as judged by immunoblotting. Further, culturing glioma cells in the presence of the global DNA demethylating agent 5-aza-2′-deoxycytidine and the histone deacetylase inhibitor Trichostatin A resulted in re-expression of TG2 in these lines. In primary brain tumors we observed that the TGM2 promoter is commonly hypermethylated and that this feature is a cancer-associated phenomenon. Using publically available databases, TG2 expression in gliomas was found to vary widely, with many tumors showing overexpression or underexpression of this gene. Since overexpression of TG2 leads to resistance to doxorubicin through the ectopic activation of NFκB, we sought to examine the effects of recombinant TG2 expression in glioma cells treated with commonly used brain tumor therapeutics. We observed that in addition to doxorubicin, TG2 expression drove resistance to CCNU; however, TG2 expression did not alter sensitivity to other drugs tested. Finally, a catalytically null mutant of TG2 was also able to support doxorubicin resistance in glioma cells indicating that transglutaminase activity is not necessary for the resistance phenotype.
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