The Level of Ets-1 Protein Is Regulated by Poly(ADP-Ribose) Polymerase-1 (PARP-1) in Cancer Cells to Prevent DNA Damage

Ets-1 is a transcription factor that regulates many genes involved in cancer progression and in tumour invasion. It is a poor prognostic marker for breast, lung, colorectal and ovary carcinomas. Here, we identified poly(ADP-ribose) polymerase-1 (PARP-1) as a novel interaction partner of Ets-1. We show that Ets-1 activates, by direct interaction, the catalytic activity of PARP-1 and is then poly(ADP-ribosyl)ated in a DNA-independent manner. The catalytic inhibition of PARP-1 enhanced Ets-1 transcriptional activity and caused its massive accumulation in cell nuclei. Ets-1 expression was correlated with an increase in DNA damage when PARP-1 was inhibited, leading to cancer cell death. Moreover, PARP-1 inhibitors caused only Ets-1-expressing cells to accumulate DNA damage. These results provide new insight into Ets-1 regulation in cancer cells and its link with DNA repair proteins. Furthermore, our findings suggest that PARP-1 inhibitors would be useful in a new therapeutic strategy that specifically targets Ets-1-expressing tumours.

Ets-1是一种转录因子，可调控诸多参与癌症进展与肿瘤侵袭的基因。其作为不良预后标志物，与乳腺癌、肺癌、结直肠癌及卵巢癌的不良预后相关。本研究鉴定出聚(ADP-核糖)聚合酶-1（poly(ADP-ribose) polymerase-1，PARP-1）为Ets-1的新型互作伴侣。研究表明，Ets-1可通过直接相互作用增强PARP-1的催化活性，随后自身以不依赖DNA的方式发生聚ADP核糖基化修饰。对PARP-1进行催化抑制，可提升Ets-1的转录活性，并使其在细胞核内大量积累。当PARP-1受到抑制时，Ets-1的表达会加剧DNA损伤，最终导致癌细胞死亡。此外，PARP-1抑制剂仅会使表达Ets-1的细胞出现DNA损伤积累。上述研究结果为癌细胞中Ets-1的调控机制及其与DNA修复蛋白的关联提供了全新视角。本研究的发现还提示，PARP-1抑制剂可应用于一种全新的治疗策略，特异性靶向表达Ets-1的肿瘤。