Yaglom Julia A, McFarland Christopher, Mirny Leonid, Sherman Michael Y
Department Biochemistry, Boston University School of Medicine, Boston, MA.
Harvard Graduate Program in Biophysics, Harvard University, Cambridge, MA.
Oncotarget. 2014 Sep 30;5(18):8367-78. doi: 10.18632/oncotarget.2259.
DNA instability is an important contributor to cancer development. Previously, defects in the chromosome segregation and excessive DNA double strand breaks due to the replication or oxidative stresses were implicated in DNA instability in cancer. Here, we demonstrate that DNA instability can directly result from the oncogene-induced senescence signaling. Expression of the activated form of Her2 oncogene, NeuT, in immortalized breast epithelial cells led to downregulation of the major DNA repair factor histone H2AX and a number of other components of the HR and NHEJ double strand DNA breaks repair pathways. H2AX expression was regulated at the transcriptional level via a senescence pathway involving p21-mediated regulation of CDK and Rb1. The p21-dependent downregulation of H2AX was seen both in cell culture and the MMTV-neu mouse model of Her2-positive breast cancer. Importantly, downregulation of H2AX upon Her2/NeuT expression impaired repair of double strand DNA breaks. This impairment resulted in both increased DNA instability in the form of somatic copy number alterations, and in increased sensitivity to the chemotherapeutic drug doxorubicin. Overall, these findings indicate that the Her2/NeuT oncogene signaling directly potentiates DNA instability and increases sensitivity to DNA damaging treatments.
DNA不稳定性是癌症发生发展的重要因素。此前，染色体分离缺陷以及复制或氧化应激导致的过多DNA双链断裂被认为与癌症中的DNA不稳定性有关。在此，我们证明DNA不稳定性可直接由癌基因诱导的衰老信号产生。在永生化乳腺上皮细胞中表达活化形式的Her2癌基因NeuT，导致主要DNA修复因子组蛋白H2AX以及HR和NHEJ双链DNA断裂修复途径的许多其他成分下调。H2AX表达通过涉及p21介导的CDK和Rb1调节的衰老途径在转录水平上受到调控。在细胞培养以及Her2阳性乳腺癌的MMTV-neu小鼠模型中均观察到p21依赖性的H2AX下调。重要的是，Her2/NeuT表达时H2AX的下调损害了双链DNA断裂的修复。这种损害导致以体细胞拷贝数改变形式出现的DNA不稳定性增加，以及对化疗药物阿霉素的敏感性增加。总体而言，这些发现表明Her2/NeuT癌基因信号直接增强DNA不稳定性并增加对DNA损伤治疗的敏感性。
