BACKGROUND E74 Like ETS Transcription Factor 3 (ELF3) functions as a transcriptional factor to regulate non-small cell lung cancer (NSCLC) differentiation and progression. Poly(ADP-ribose) polymerase (PARP) inhibitors demonstrate anti-tumor effect in NSCLC. This study aimed to investigate whether ELF3 confers synthetic lethal with PARP inhibitor in NSCLC. MATERIALS AND METHODS The sensitivity of PARP inhibitor, Olaparib, to different NSCLC cell lines was determined by half maximal inhibitory concentration (IC50). Expression of ELF3 in NSCLC cell lines was evaluated by western blot. The effects of ELF3 on cytotoxicity of Olaparib to NSCLC were investigated by MTT (3-(4,5- di methyl thiazol -2-yl)-2,5-di phenyl tetrazolium bromide) and colony formation assays. The underlying mechanism involved in synthetic lethality with ELF3 and PARP inhibitors in NSCLC were detected by immunofluorescence and Western blot. RESULTS ELF3 was up-regulated in NSCLC cell lines exhibiting resistance to PARP inhibitor, Olaparib. Knock down of ELF3 decreased the sensitivity and enhanced cytotoxicity of Olaparib to NSCLC cells. Moreover, knock down of ELF3 increased S139 phosphorylated histone H2AX (γH2AX), and inhibited homologous recombination activity via down-regulation of DNA repair protein RAD51 homolog 1 (RAD51), thus showing deficiency in DNA damage repair. Over-expression of ELF3 could up-regulate phosphorylation of AKT (Protein kinase B), while knock down of ELF3 regulated homologous recombination-mediated DNA repair via down-regulation of phosphorylation of AKT. CONCLUSION Knock down of ELF3 revealed homologous recombination deficiency via AKT signaling pathway, and synthetic lethality with ELF3 inhibition and PARP inhibitor indicated the clinical significance of PARP inhibitor in ELF3-deficient NSCLC.

中文翻译：

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ELF3的抑制赋予了PARP抑制剂在非小细胞肺癌中的合成杀伤力

背景 E74 与 ETS 转录因子 3 (ELF3) 一样，作为转录因子发挥调节非小细胞肺癌 (NSCLC) 分化和进展的作用。聚 (ADP-核糖) 聚合酶 (PARP) 抑制剂在 NSCLC 中表现出抗肿瘤作用。本研究旨在调查 ELF3 是否赋予 PARP 抑制剂在 NSCLC 中的合成致死性。材料和方法 PARP 抑制剂奥拉帕尼对不同 NSCLC 细胞系的敏感性通过半数最大抑制浓度 (IC50) 确定。通过蛋白质印迹评估ELF3在NSCLC细胞系中的表达。通过MTT（3-（4,5-二甲基噻唑-2-基）-2,5-二苯基溴化四唑）和集落形成测定研究ELF3对奥拉帕尼对NSCLC的细胞毒性的影响。通过免疫荧光和蛋白质印迹检测 ELF3 和 PARP 抑制剂在 NSCLC 中的合成致死性的潜在机制。结果 ELF3 在表现出对 PARP 抑制剂奥拉帕尼耐药的 NSCLC 细胞系中上调。敲低 ELF3 降低了奥拉帕尼对 NSCLC 细胞的敏感性并增强了细胞毒性。此外，敲除 ELF3 可增加 S139 磷酸化组蛋白 H2AX (γH2AX)，并通过下调 DNA 修复蛋白 RAD51 同源物 1 (RAD51) 抑制同源重组活性，从而显示 DNA 损伤修复不足。ELF3 的过表达可以上调 AKT（蛋白激酶 B）的磷酸化，而 ELF3 的敲低通过下调 AKT 的磷酸化来调节同源重组介导的 DNA 修复。