Amarsanaa Enkhzul, Wie Minwoo, Shin Unbeom, Bilal Nabeela, Hwang Jungme, Lee Eun A, Lee Seon Young, Kim Byung-Gyu, Kim Shinseog, Lee Yoonsung, Myung Kyungjae
Center for Genomic Integrity, Institute for Basic Science, Ulsan 44919, Republic of Korea.
Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea.
NAR Cancer. 2025 Apr 30;7(2):zcaf013. doi: 10.1093/narcan/zcaf013. eCollection 2025 Jun.
Targeted therapy leveraging synthetic lethality in homologous recombination (HR)-defective tumors, particularly in BRCA-mutated tumors through poly(ADP-ribose) polymerase (PARP)-dependent repair inhibition, has shown success. However, the challenge lies in the ability of the tumors to reactivate HR via diverse mechanisms, leading to resistance against PARP-dependent repair inhibition. Addressing this issue, the down-regulation of HR activity has been explored as a potential strategy to overcome PARP inhibitor-resistant tumors. Yet, the intricate modulation of HR gene expression in mammalian cells is still not fully understood. In this study, we used a small molecule, UNI66, identified from high-throughput screening, to investigate regulatory mechanisms of HR. UNI66 was observed to induce synthetic lethality in PARP1-deficient cells and enhanced the sensitivity of multiple cancer cells to PARP inhibitors, suggesting a role in HR down-regulation. Mechanistically, UNI66 was found to interact with and inhibit BRD4 protein binding to the promoters of and genes, resulting in the down-regulation of their transcription. This decrease in and expression was associated with reduced HR activity, thereby increasing the sensitivity of tumors to PARP inhibitors. These findings indicate that BRD4-mediated transcriptional regulation of and influences HR activity, which may have implications for overcoming resistance to PARP inhibitors.
利用同源重组（HR）缺陷肿瘤中的合成致死性进行靶向治疗，尤其是通过抑制聚（ADP-核糖）聚合酶（PARP）依赖的修复来治疗BRCA突变肿瘤，已取得成功。然而，挑战在于肿瘤能够通过多种机制重新激活HR，从而导致对PARP依赖的修复抑制产生抗性。为了解决这个问题，人们探索了下调HR活性作为克服PARP抑制剂耐药肿瘤的潜在策略。然而，哺乳动物细胞中HR基因表达的复杂调控仍未完全了解。在本研究中，我们使用了一种从高通量筛选中鉴定出的小分子UNI66来研究HR的调控机制。观察到UNI66在PARP1缺陷细胞中诱导合成致死性，并增强了多种癌细胞对PARP抑制剂的敏感性，表明其在下调HR中发挥作用。从机制上讲，发现UNI66与BRD4蛋白相互作用并抑制其与 和 基因启动子的结合，导致它们的转录下调。 和 表达的这种降低与HR活性降低相关，从而增加了肿瘤对PARP抑制剂的敏感性。这些发现表明，BRD4介导的对 和 的转录调控影响HR活性，这可能对克服对PARP抑制剂的抗性具有重要意义。
