Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang 110122, Liaoning Province, PR China.
Department of Intelligent Computation, School of Intelligent Medicine, China Medical University, Shenyang 110122, Liaoning Province, PR China.
Cell Signal. 2024 Jun;118:111151. doi: 10.1016/j.cellsig.2024.111151. Epub 2024 Mar 22.
Chemoresistance poses a significant obstacle to the treatment of breast cancer patients. The increased capacity of DNA damage repair is one of the mechanisms underlying chemoresistance. Bioinformatic analyses showed that E2F8 was associated with cell cycle progression and homologous recombination (HR) repair of DNA double-strand breaks (DSBs) in breast cancer. E2F8 knockdown suppressed cell growth and attenuated HR repair. Accordingly, E2F8 knockdown sensitized cancer cells to Adriamycin and Cisplatin. Centromere protein L (CENPL) is a transcriptional target by E2F8. CENPL overexpression in E2F8-knockdowned cells recovered at least in part the effect of E2F8 on DNA damage repair and chemotherapy sensitivity. Consistently, CENPL knockdown impaired DNA damage repair and sensitized cancer cells to DNA-damaging drugs. These findings demonstrate that targeting E2F8-CENPL pathway is a potential approach to overcoming chemoresistance.
化学耐药性是乳腺癌患者治疗的重大障碍。DNA 损伤修复能力的增加是化学耐药性的机制之一。生物信息学分析表明，E2F8 与乳腺癌细胞周期进程和同源重组（HR）修复 DNA 双链断裂（DSBs）有关。E2F8 敲低抑制细胞生长并减弱 HR 修复。因此，E2F8 敲低使癌细胞对阿霉素和顺铂敏感。着丝粒蛋白 L（CENPL）是 E2F8 的转录靶标。E2F8 敲低细胞中 CENPL 的过表达至少部分恢复了 E2F8 对 DNA 损伤修复和化疗敏感性的作用。一致地，CENPL 敲低损害 DNA 损伤修复并使癌细胞对 DNA 损伤药物敏感。这些发现表明，靶向 E2F8-CENPL 途径是克服化学耐药性的一种潜在方法。
