Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA.
Cancer Res. 2013 Jan 15;73(2):1000-10. doi: 10.1158/0008-5472.CAN-12-3538. Epub 2012 Dec 7.
Topoisomerase II (TOP2)-targeting poisons such as anthracyclines and etoposide are commonly used for cancer chemotherapy and kill tumor cells by causing accumulation of DNA double-strand breaks (DSB). Several lines of evidence indicate that overexpression of TOP2A, the gene encoding topoisomerase IIα, increases sensitivity of tumor cells to TOP2 poisons, but it is not clear why some TOP2A-overexpressing (TOP2A-High) tumors respond poorly to these drugs. In this study, we identified that TOP2A expression is induced by DLX4, a homeoprotein that is overexpressed in breast and ovarian cancers. Analysis of breast cancer datasets revealed that TOP2A-high cases that also highly expressed DLX4 responded more poorly to anthracycline-based chemotherapy than TOP2A-high cases that expressed DLX4 at low levels. Overexpression of TOP2A alone in tumor cells increased the level of DSBs induced by TOP2 poisons. In contrast, DLX4 reduced the level of TOP2 poison-induced DSBs irrespective of its induction of TOP2A. DLX4 did not stimulate homologous recombination-mediated repair of DSBs. However, DLX4 interacted with Ku proteins, stimulated DNA-dependent protein kinase activity, and increased erroneous end-joining repair of DSBs. Whereas DLX4 did not reduce levels of TOP2 poison-induced DSBs in Ku-deficient cells, DLX4 stimulated DSB repair and reduced the level of TOP2 poison-induced DSBs when Ku was reconstituted in these cells. Our findings indicate that DLX4 induces TOP2A expression but reduces sensitivity of tumor cells to TOP2 poisons by stimulating Ku-dependent repair of DSBs. These opposing activities of DLX4 could explain why some TOP2A-overexpressing tumors are not highly sensitive to TOP2 poisons.
拓扑异构酶 II（TOP2）靶向毒物，如蒽环类药物和依托泊苷，常用于癌症化疗，通过引起 DNA 双链断裂（DSB）来杀死肿瘤细胞。有几条证据表明，TOP2A 基因（编码拓扑异构酶 IIα）的过度表达会增加肿瘤细胞对 TOP2 毒物的敏感性，但尚不清楚为什么一些 TOP2A 过表达（TOP2A-高）的肿瘤对这些药物反应不佳。在这项研究中，我们发现 DLX4（一种在家蛋白中过表达的蛋白）可诱导 TOP2A 的表达。对乳腺癌数据集的分析表明，与 DLX4 低表达的 TOP2A-高病例相比，TOP2A-高且 DLX4 高表达的病例对基于蒽环类的化疗反应更差。肿瘤细胞中 TOP2A 的过表达本身就会增加 TOP2 毒物诱导的 DSB 水平。相反，DLX4 降低了 TOP2 毒物诱导的 DSB 水平，而与诱导 TOP2A 无关。DLX4 不会刺激同源重组介导的 DSB 修复。然而，DLX4 与 Ku 蛋白相互作用，刺激 DNA 依赖性蛋白激酶活性，并增加 DSB 的错误末端连接修复。虽然 DLX4 不能降低 Ku 缺陷细胞中 TOP2 毒物诱导的 DSB 水平，但 DLX4 刺激 DSB 修复并降低 Ku 在这些细胞中重建时 TOP2 毒物诱导的 DSB 水平。我们的研究结果表明，DLX4 通过刺激 Ku 依赖性 DSB 修复来诱导 TOP2A 的表达，但降低了肿瘤细胞对 TOP2 毒物的敏感性。DLX4 的这些相反的活性可以解释为什么一些 TOP2A 过表达的肿瘤对 TOP2 毒物不高度敏感。
