叉头框蛋白 P3 通过转录抑制 BRCA1 调节癌细胞对辐射的敏感性。
FOXP3 regulates sensitivity of cancer cells to irradiation by transcriptional repression of BRCA1.
机构信息
Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
出版信息
Cancer Res. 2013 Apr 1;73(7):2170-80. doi: 10.1158/0008-5472.CAN-12-2481. Epub 2013 Jan 14.
Abstract
FOXP3 is an X-linked tumor suppressor gene and a master regulator in T regulatory cell function. This gene has been found to be mutated frequently in breast and prostate cancers and to inhibit tumor cell growth, but its functional significance in DNA repair has not been studied. We found that FOXP3 silencing stimulates homologous recombination-mediated DNA repair and also repair of γ-irradiation-induced DNA damage. Expression profiling and chromatin-immunoprecipitation analyses revealed that FOXP3 regulated the BRCA1-mediated DNA repair program. Among 48 FOXP3-regulated DNA repair genes, BRCA1 and 12 others were direct targets of FOXP3 transcriptional control. Site-specific interaction of FOXP3 with the BRCA1 promoter repressed its transcription. Somatic FOXP3 mutants identified in breast cancer samples had reduced BRCA1 repressor activity, whereas FOXP3 silencing and knock-in of a prostate cancer-derived somatic FOXP3 mutant increased the radioresistance of cancer cells. Together our findings provide a missing link between FOXP3 function and DNA repair programs.
摘要
叉头框蛋白 P3（FOXP3）是一种 X 连锁的肿瘤抑制基因，也是调节性 T 细胞功能的主要调控因子。该基因在乳腺癌和前列腺癌中经常发生突变，并能抑制肿瘤细胞生长，但它在 DNA 修复中的功能意义尚未得到研究。我们发现，FOXP3 沉默可刺激同源重组介导的 DNA 修复，也可修复 γ 射线诱导的 DNA 损伤。表达谱分析和染色质免疫沉淀分析显示，FOXP3 调控 BRCA1 介导的 DNA 修复程序。在 48 个 FOXP3 调控的 DNA 修复基因中，BRCA1 和其他 12 个基因是 FOXP3 转录控制的直接靶点。FOXP3 与 BRCA1 启动子的特异性相互作用抑制其转录。在乳腺癌样本中发现的体细胞 FOXP3 突变体其 BRCA1 抑制活性降低，而 FOXP3 沉默和前列腺癌衍生的体细胞 FOXP3 突变体的敲入则增加了癌细胞的放射抗性。总之，我们的研究结果提供了 FOXP3 功能与 DNA 修复程序之间缺失的一环。
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