Department of Human Anatomy and Cell Science, Faculty of Medicine, University of Manitoba, Winnipeg, Canada.
Neoplasia. 2013 Mar;15(3):263-80. doi: 10.1593/neo.121988.
The non-histone chromatin binding protein high mobility group AT-hook 2 (HMGA2) is expressed in stem cells and many cancer cells, including tumor initiating cells, but not translated in normal human somatic cells. The presence of HMGA2 is correlated with advanced neoplastic disease and poor prognosis for patients. We had previously demonstrated a role of HMGA2 in DNA repair pathways. In the present study, we employed different human tumor cell models with endogenous and exogenous expression of HMGA2 and show that upon DNA damage, the presence of HMGA2 caused an increased and sustained phosphorylation of the ataxia telangiectasia and Rad3-related kinase (ATR) and its downstream target checkpoint kinase 1 (CHK1). The presence of activated pCHK1(Ser296) coincided with prolonged G2/M block and increased tumor cell survival, which was enhanced further in the presence of HMGA2. Our study, thus, identifies a novel relationship between the ATR-CHK1 DNA damage response pathway and HMGA2, which may support the DNA repair function of HMGA2 in cancer cells. Furthermore, our data provide a rationale for the use of inhibitors to ATR or CHK1 and HMGA2 in the treatment of HMGA2-positive human cancer cells.
非组蛋白染色质结合蛋白高迁移率族 AT 钩 2（HMGA2）在干细胞和许多癌细胞中表达，包括肿瘤起始细胞，但在正常人类体细胞中不翻译。HMGA2 的存在与晚期肿瘤疾病和患者预后不良相关。我们之前已经证明了 HMGA2 在 DNA 修复途径中的作用。在本研究中，我们使用了具有内源性和外源性 HMGA2 表达的不同人肿瘤细胞模型，并表明在 DNA 损伤后，HMGA2 的存在导致共济失调毛细血管扩张症和 Rad3 相关激酶（ATR）及其下游靶标检查点激酶 1（CHK1）的磷酸化增加和持续。激活的 pCHK1（Ser296）的存在与延长的 G2/M 阻断和增加的肿瘤细胞存活相关，在存在 HMGA2 的情况下进一步增强。因此，我们的研究确定了 ATR-CHK1 DNA 损伤反应途径与 HMGA2 之间的新关系，这可能支持 HMGA2 在癌细胞中的 DNA 修复功能。此外，我们的数据为使用 ATR 或 CHK1 和 HMGA2 的抑制剂治疗 HMGA2 阳性人癌细胞提供了依据。
