Department of Gynecology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China; Branch Of National Clinical Research Center For Gynecology and Obstetrics, China; Maternal and Child Center Laboratory, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Department of Gynecology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China; Branch Of National Clinical Research Center For Gynecology and Obstetrics, China.
Cancer Lett. 2024 Aug 10;597:217064. doi: 10.1016/j.canlet.2024.217064. Epub 2024 Jun 14.
Platinum-based chemotherapy causes genetic damage and induces apoptosis in ovarian cancer cells. Enhancing the ability to resist platinum drug-induced DNA damage and apoptotic stress is critical for tumor cells to acquire drug resistance. Here, we found that Y-box binding protein 1 (YBX1) was highly expressed in cisplatin-resistant patient-derived organoids (PDOs) and was a crucial gene for alleviating platinum-induced stress and maintaining drug resistance characteristics in ovarian cancer cells. Mechanistically, YBX1 recognized m5C modifications in CHD3 mRNA and maintained mRNA stability by recruiting PABPC1 protein. This regulatory process enhanced chromatin accessibility and improved the efficiency of homologous recombination (HR) repair, facilitating tumor cells to withstand platinum-induced apoptotic stress. In addition, SU056, an inhibitor of YBX1, exhibited the potential to reverse platinum resistance in subcutaneous and PDO orthotopic xenograft models. In conclusion, YBX1 is critical for ovarian cancer cells to alleviate the platinum-induced stress and may be a potential target for reversing drug-resistant therapies.
铂类化疗会导致卵巢癌细胞的遗传损伤，并诱导其凋亡。增强抵抗铂类药物诱导的 DNA 损伤和凋亡应激的能力，对于肿瘤细胞获得耐药性至关重要。在这里，我们发现 Y 盒结合蛋白 1（YBX1）在顺铂耐药的患者来源类器官（PDO）中高度表达，是缓解铂类诱导的应激和维持卵巢癌细胞耐药特征的关键基因。从机制上讲，YBX1 识别 CHD3 mRNA 中的 m5C 修饰，并通过募集 PABPC1 蛋白来维持 mRNA 的稳定性。这个调节过程增强了染色质的可及性，并提高了同源重组（HR）修复的效率，使肿瘤细胞能够耐受铂类诱导的凋亡应激。此外，YBX1 的抑制剂 SU056 在皮下和 PDO 原位移植模型中表现出逆转铂类耐药的潜力。总之，YBX1 对于卵巢癌细胞缓解铂类诱导的应激至关重要，可能是逆转耐药治疗的潜在靶点。
