Downregulation of BRCA1-BRCA2-containing complex subunit 3 sensitizes glioma cells to temozolomide.
Downregulation of BRCA1-BRCA2-containing complex subunit 3 sensitizes glioma cells to temozolomide.
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DOI：
10.18632/oncotarget.2543
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发表时间：
2014-11-15
期刊：
影响因子：
--
通讯作者：
Tzeng SF
中科院分区：
文献类型：
--
作者：
Chai KM;Wang CY;Liaw HJ;Fang KM;Yang CS;Tzeng SF
我们先前发现BRCA1-BRCA2-包含复合亚单位3(BRCC3)在致瘤大鼠神经胶质瘤细胞中高表达。然而，BRCC3在人脑胶质瘤细胞中的功能作用仍有待研究。本研究表明，烷化剂替莫唑胺(TMZ)可诱导人恶性胶质母细胞瘤U251和A172细胞株BRCC3表达上调。TMZ处理U251和A172细胞后，依赖于同源重组(HR)的DNA修复相关基因(BRCA1、BRCA2、RAD51和FANCD2)也增加。慢病毒介导的BRCC3基因敲除方法不仅显著降低了U251和A172细胞的克隆形成和迁移能力，而且增强了它们对TMZ的敏感性。磷酸化H_2AX焦点(γH_2AX)的形成增加，这是DNA损伤的一个指标，在稳定下调BRCC3表达的胶质瘤细胞中持续存在，表明BRCC3基因缺陷与DNA修复损伤有关。综上所述，我们证明通过诱导DNA修复，BRCC3使胶质瘤细胞对TMZ产生抗药性。这一发现表明BRCC3是治疗烷化耐药胶质瘤的潜在靶点。
We previously found that BRCA1-BRCA2-containing complex subunit 3 (BRCC3) was highly expressed in tumorigenic rat glioma cells. However, the functional role of BRCC3 in human glioma cells remains to be characterized. This study indicated that the upregulation of BRCC3 expression was induced in two human malignant glioblastoma U251 and A172 cell lines following exposure to the alkylating agent, temozolomide (TMZ). Homologous recombination (HR)-dependent DNA repair-associated genes (i.e. BRCA1, BRCA2, RAD51 and FANCD2) were also increased in U251 and A172 cells after treatment with TMZ. BRCC3 gene knockdown through lentivirus-mediated gene knockdown approach not only significantly reduced the clonogenic and migratory abilities of U251 and A172 cells, but also enhanced their sensitization to TMZ. The increase in phosphorylated H2AX foci (γH2AX) formation, an indicator of DNA damage, persisted in TMZ-treated glioma cells with stable knockdown BRCC3 expression, suggesting that BRCC3 gene deficiency is associated with DNA repair impairment. In summary, we demonstrate that by inducing DNA repair, BRCC3 renders glioma cells resistant to TMZ. The findings point to BRCC3 as a potential target for treatment of alkylating drug-resistant glioma.
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