Chattopadhyay Ranajoy, Das Soumita, Maiti Amit K, Boldogh Istvan, Xie Jingwu, Hazra Tapas K, Kohno Kimitoshi, Mitra Sankar, Bhakat Kishor K
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77555-1079, USA.
Mol Cell Biol. 2008 Dec;28(23):7066-80. doi: 10.1128/MCB.00244-08. Epub 2008 Sep 22.
Human AP-endonuclease (APE1/Ref-1), a central enzyme involved in the repair of oxidative base damage and DNA strand breaks, has a second activity as a transcriptional regulator that binds to several trans-acting factors. APE1 overexpression is often observed in tumor cells and confers resistance to various anticancer drugs; its downregulation sensitizes tumor cells to such agents. Because the involvement of APE1 in repairing the DNA damage induced by many of these drugs is unlikely, drug resistance may be linked to APE1's transcriptional regulatory function. Here, we show that APE1, preferably in the acetylated form, stably interacts with Y-box-binding protein 1 (YB-1) and enhances its binding to the Y-box element, leading to the activation of the multidrug resistance gene MDR1. The enhanced MDR1 level due to the ectopic expression of wild-type APE1 but not of its nonacetylable mutant underscores the importance of APE1's acetylation in its coactivator function. APE1 downregulation sensitizes MDR1-overexpressing tumor cells to cisplatin or doxorubicin, showing APE1's critical role in YB-1-mediated gene expression and, thus, drug resistance in tumor cells. A systematic increase in both APE1 and MDR1 expression was observed in non-small-cell lung cancer tissue samples. Thus, our study has established the novel role of the acetylation-mediated transcriptional regulatory function of APE1, making it a potential target for the drug sensitization of tumor cells.
人脱嘌呤嘧啶内切核酸酶（APE1/Ref-1）是一种参与氧化碱基损伤修复和DNA链断裂修复的关键酶，它还具有作为转录调节因子的第二种活性，可与多种反式作用因子结合。APE1过表达在肿瘤细胞中经常可见，并赋予对多种抗癌药物的抗性；其下调可使肿瘤细胞对这些药物敏感。由于APE1不太可能参与修复许多这类药物诱导的DNA损伤，因此耐药性可能与APE1的转录调节功能有关。在此，我们表明，APE1，尤其是乙酰化形式的APE1，与Y盒结合蛋白1（YB-1）稳定相互作用，并增强其与Y盒元件的结合，从而导致多药耐药基因MDR1的激活。由于野生型APE1而非其不可乙酰化突变体的异位表达导致MDR1水平升高，这突出了APE1乙酰化在其共激活功能中的重要性。APE1下调使过表达MDR1的肿瘤细胞对顺铂或阿霉素敏感，表明APE1在YB-1介导的基因表达中起关键作用，进而在肿瘤细胞耐药中起关键作用。在非小细胞肺癌组织样本中观察到APE1和MDR1表达均系统性增加。因此，我们的研究确立了APE1乙酰化介导的转录调节功能的新作用，使其成为肿瘤细胞药物增敏的潜在靶点。
