Cao Congcong, Li Aolin, Xu Chaojie, Wu Baorui, Yao Lin, Liu Yuchen
Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Institute of Translational Medicine, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Synthetic Biology Research Center, Health Science Center, Shenzhen University, Shenzhen, China.
Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China.
Nat Chem Biol. 2025 Mar;21(3):393-401. doi: 10.1038/s41589-024-01719-w. Epub 2024 Aug 30.
Targeted protein degradation has become a notable drug development strategy, but its application has been limited by the dependence on protein-based chimeras with restricted genetic manipulation capabilities. The use of long non-coding RNAs (lncRNAs) has emerged as a viable alternative, offering interactions with cellular proteins to modulate pathways and enhance degradation capabilities. Here we introduce a strategy employing artificial lncRNAs (alncRNAs) for precise targeted protein degradation. By integrating RNA aptamers and sequences from the lncRNA HOTAIR, our alncRNAs specifically target and facilitate the ubiquitination and degradation of oncogenic transcription factors and tumor-related proteins, such as c-MYC, NF-κB, ETS-1, KRAS and EGFR. These alncRNAs show potential in reducing malignant phenotypes in cells, both in vitro and in vivo, offering advantages in efficiency, adaptability and versatility. This research enhances knowledge of lncRNA-driven protein degradation and presents an effective method for targeted therapies.
靶向蛋白质降解已成为一种显著的药物开发策略，但其应用受到对具有有限基因操作能力的基于蛋白质的嵌合体的依赖的限制。长链非编码RNA（lncRNA）的使用已成为一种可行的替代方案，它能与细胞蛋白相互作用以调节信号通路并增强降解能力。在此，我们介绍一种利用人工lncRNA（alnRNA）进行精确靶向蛋白质降解的策略。通过整合RNA适体和lncRNA HOTAIR的序列，我们的alnRNA特异性靶向并促进致癌转录因子和肿瘤相关蛋白（如c-MYC、NF-κB、ETS-1、KRAS和EGFR）的泛素化和降解。这些alnRNA在体外和体内细胞中均显示出减少恶性表型的潜力，在效率、适应性和通用性方面具有优势。本研究增进了对lncRNA驱动的蛋白质降解的认识，并提出了一种有效的靶向治疗方法。
