Yang Yanting, Li Zongcheng, Yu Xinyuan, Zheng Yanxiu, Yu Yongquan, Yang Ming, Zhang Nasha
Shandong Provincial Key Laboratory of Precision Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, 250117, China.
Shandong Provincial Key Laboratory of Precision Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, 250117, China; Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, 250117, China.
Cancer Lett. 2025 Aug 10;625:217757. doi: 10.1016/j.canlet.2025.217757. Epub 2025 May 2.
Radiotherapy is an important management for non-small cell lung cancer (NSCLC). Although long non-coding RNAs (lncRNAs) have been reported to be involved in modulating radiosensitivity, the underlying mechanisms are still largely unclear. Here, we found that tumor suppressor WDR11-DT is a novel radiation-induced lncRNA, which is transcriptionally regulated by SPDEF, in NSCLC. In contrast to normal tissues, WDR11-DT is down-regulated in NSCLC specimens and its low expression was associated with poor prognosis of patient receiving radiotherapy. Importantly, WDR11-DT can markedly enhance NSCLC cells' radiosensitivity in vitro and in vivo. WDR11-DT functions through distinct mechanisms via binding different proteins. WDR11-DT facilitates interactions between PARP1 and its E3 ligase TRIP12, promotes PARP1 protein degradation and suppresses PARP1-controlled Single-strand breaks (SSBs) repair. Additionally, WDR11-DT binds RNA-bind protein HNRNPK, represses its functions in improving RNA stability of homologous recombination (HR) genes, decreases expression of BRCA1, ATM, BLM and RAD50, and suppresses radiotherapy-triggered HR repair. WDR11-DT-induced dual restraints of PARP1 and the HR pathway lead to the accumulation of double-strand breaks as well as synthetic lethal effects of malignant cells, which, thereby, enhances radiosensitivity and inhibits progression of lung cancer. These results extend our current knowledge of radio-biology and elucidate that WDR11-DT may be a new target for boosting cancer radiotherapy.
放射治疗是非小细胞肺癌（NSCLC）的重要治疗手段。尽管已有报道称长链非编码RNA（lncRNA）参与调节放射敏感性，但其潜在机制仍不清楚。在此，我们发现肿瘤抑制因子WDR11-DT是一种新的辐射诱导lncRNA，在NSCLC中受SPDEF转录调控。与正常组织相比，WDR11-DT在NSCLC标本中表达下调，其低表达与接受放疗患者的不良预后相关。重要的是，WDR11-DT在体外和体内均可显著增强NSCLC细胞的放射敏感性。WDR11-DT通过结合不同蛋白质发挥不同机制的作用。WDR11-DT促进PARP1与其E3连接酶TRIP12之间的相互作用，促进PARP1蛋白降解，抑制PARP1控制的单链断裂（SSB）修复。此外，WDR11-DT结合RNA结合蛋白HNRNPK，抑制其在提高同源重组（HR）基因RNA稳定性方面的功能，降低BRCA1、ATM、BLM和RAD50的表达，并抑制放疗触发的HR修复。WDR11-DT对PARP1和HR途径的双重抑制导致双链断裂的积累以及恶性细胞的合成致死效应，从而增强放射敏感性并抑制肺癌进展。这些结果扩展了我们目前对放射生物学的认识，并阐明WDR11-DT可能是提高癌症放疗效果的新靶点。
