Targeting bromodomain protein ANCCA/ATAD2 enhances the efficacy of DNA-damaging chemotherapy agents and radiation
Targeting bromodomain protein ANCCA/ATAD2 enhances the efficacy of DNA-damaging chemotherapy agents and radiation
复制标题
DOI：
10.3892/or.2019.7418
复制
发表时间：
2020-01-01
期刊：
影响因子：
4.2
通讯作者：
Chen, Hong-Wu
中科院分区：
文献类型：
--
作者：
Duan, Zhijian;Andrews, Nicolas P.;Chen, Hong-Wu
BRD4 染色质调节因子等溴结构域蛋白是有吸引力的癌症治疗靶点。 ANCCA（AAA+核共调节癌症相关蛋白，也称为含有 2 或 ATAD2 的 ATPase 家族 AAA 结构域）是一种新型肿瘤药物靶点，包含一个溴结构域和一个 ATPase 结构域。我们的研究小组以及其他人之前将 ANCCA/ATAD2 确定为一种假定的癌基因，并且是包括三阴性乳腺癌 (TNBC) 在内的许多类型癌症的不良预后因素。在本研究中，首次报道了DNA损伤性化疗药物如卡铂、阿霉素和丝裂霉素C以及电离辐射高度诱导ANCCA的表达。值得注意的是，ANCCA 是有效溶解 DNA 损伤灶和同源重组所必需的。进一步的研究表明，ANCCA 介导 DNA 损伤反应和修复因子（包括 Chk1、Chk2 和 BRCA1）的最佳表达和激活，并且 ANCCA 被招募到 BRCA1 的启动子以响应 DNA 损伤。此外，ANCCA 敲低使 TNBC 细胞对卡铂敏感。总的来说，这些数据提供了第一个证据，表明 ANCCA 是 DNA 损伤反应和修复的新型介质，并且靶向 ANCCA 可以增强放射和化疗的疗效。
Bromodomain proteins such as BRD4 chromatin regulator are attractive cancer therapeutic targets. ANCCA (AAA+ nuclear coregulatory cancer-associated protein, also known as ATPase family AAA domain containing 2 or ATAD2) is a novel oncology drug target and contains a bromodomain and an ATPase domain. Our research group as well as others previously identified ANCCA/ATAD2 as a putative oncogene and a poor prognosis factor in many types of cancer including triple-negative breast cancer (TNBC). In the present study, it is reported for the first time that the expression of ANCCA was highly induced by DNA-damaging chemotherapy agents such as carboplatin, doxorubicin and mitomycin C, as well as ionizing radiation. Notably, ANCCA is required for efficient dissolution of DNA damage foci and homologous recombination. Further studies revealed that ANCCA mediates the optimal expression and activation of DNA damage response and repair factors including Chk1, Chk2 and BRCA1, and that ANCCA is recruited to the promoter of BRCA1 in response to DNA damage. Moreover, ANCCA knockdown sensitizes TNBC cells to carboplatin. Collectively, these data provide the first evidence indicating that ANCCA is a novel mediator of DNA damage response and repair and that targeting ANCCA can enhance the efficacy of radiation and chemotherapies.