Zhu Dagao, Lu Mingliang, Cheng Hongmin
Department of Radiation Oncology, The Affiliated Tongling Hospital of Bengbu Medical University, No. 468 Bijiashan Road, Tongguan District, Tongling, 244000, China.
Department of Radiation Oncology, The People's Hospital of Tongling City, No. 468 Bijiashan Road, Tongguan District, Tongling, 244000, China.
Open Life Sci. 2025 Mar 18;20(1):20251065. doi: 10.1515/biol-2025-1065. eCollection 2025.
Radiotherapy (RT) resistance in non-small cell lung cancer (NSCLC) is a significant contributor to tumor recurrence. NAT10, an enzyme that catalyzes ac4C RNA modification, has an unclear role in RT resistance. This study aimed to explore the function of NAT10 in RT resistance in NSCLC. RT-resistant NSCLC cell lines (PC9R and A549R) were established through repeated irradiation. The impact of NAT10 on cellular immunity was evaluated by measuring immune cell populations, cytotoxicity levels, and markers of cell dysfunction. Results demonstrated elevated levels of ac4C and NAT10 in RT-resistant cells. Knockdown of NAT10 suppressed cell proliferation and enhanced immune function in PC9R and A549R cells by upregulating TNF-α and IFN-γ while downregulating PD-1 and TIM-3. Mechanistically, RT resistance in NSCLC was mediated by NAT10-dependent ac4C modification of KPNB1. Furthermore, KPNB1 facilitated PD-L1 nuclear translocation, promoting immune escape in RT-resistant NSCLC cells. Overexpression of KPNB1 enhanced cell proliferation but impaired immune function in RT-resistant NSCLC cells. In conclusion, this study demonstrates that NAT10 upregulates KPNB1 expression through ac4C modification, thereby promoting RT resistance in NSCLC via PD-L1 nuclear translocation. These findings reveal a novel mechanism underlying RT resistance in NSCLC.
非小细胞肺癌（NSCLC）中的放疗（RT）抗性是肿瘤复发的一个重要因素。NAT10是一种催化ac4C RNA修饰的酶，其在RT抗性中的作用尚不清楚。本研究旨在探讨NAT10在NSCLC放疗抗性中的功能。通过反复照射建立了放疗抗性NSCLC细胞系（PC9R和A549R）。通过测量免疫细胞群体、细胞毒性水平和细胞功能障碍标志物来评估NAT10对细胞免疫的影响。结果表明，放疗抗性细胞中ac4C和NAT10水平升高。敲低NAT10可通过上调TNF-α和IFN-γ，同时下调PD-1和TIM-3来抑制PC9R和A549R细胞的增殖并增强免疫功能。机制上，NSCLC中的放疗抗性由NAT10依赖的KPNB1的ac4C修饰介导。此外，KPNB1促进PD-L1核转位，促进放疗抗性NSCLC细胞的免疫逃逸。KPNB1的过表达增强了放疗抗性NSCLC细胞的增殖，但损害了其免疫功能。总之，本研究表明NAT10通过ac4C修饰上调KPNB1表达，从而通过PD-L1核转位促进NSCLC中的放疗抗性。这些发现揭示了NSCLC放疗抗性的一种新机制。
