Zhang Xiaoyu, Ding Tianyi, Yang Fan, Xu Haowen, Zhang Jixing, Bai Yiran, Shi Yibing, Yang Jiaqi, Chen Chaoqun, Zhang He
State Key Laboratory of Cardiology and Medical Innovation Center, Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Research Center for Stem Cells, School of Life Science and Technology, Tongji University, Shanghai, 200092, China.
Jiangxi Province Key Laboratory of Organ Development and Epigenetics, Clinical Medical Research Center, Affiliated Hospital of Jinggangshan University, Medical Department of Jinggangshan University, Ji'an, 343009, China.
Cell Death Discov. 2024 May 23;10(1):249. doi: 10.1038/s41420-024-02018-y.
Multiple gene abnormalities are major drivers of tumorigenesis. NF-κB p65 overactivation and cGAS silencing are important triggers and genetic defects that accelerate tumorigenesis. However, the simultaneous correction of NF-κB p65 and cGAS abnormalities remains to be further explored. Here, we propose a novel Induced Dual-Target Rebalance (IDTR) strategy for simultaneously correcting defects in cGAS and NF-κB p65. By using our IDTR approach, we showed for the first time that oncolytic adenovirus H101 could reactivate silenced cGAS, while silencing GAU1 long noncoding RNA (lncRNA) inhibited NF-κB p65 overactivation, resulting in efficient in vitro and in vivo antitumor efficacy in colorectal tumors. Intriguingly, we further demonstrated that oncolytic adenoviruses reactivated cGAS by promoting H3K4 trimethylation of the cGAS promoter. In addition, silencing GAU1 using antisense oligonucleotides significantly reduced H3K27 acetylation at the NF-κB p65 promoter and inhibited NF-κB p65 transcription. Our study revealed an aberrant therapeutic mechanism underlying two tumor defects, cGAS and NF-κB p65, and provided an alternative IDTR approach based on oncolytic adenovirus and antisense oligonucleotides for efficient therapeutic efficacy in tumors.
多种基因异常是肿瘤发生的主要驱动因素。NF-κB p65的过度激活和cGAS的沉默是加速肿瘤发生的重要触发因素和基因缺陷。然而，同时纠正NF-κB p65和cGAS异常仍有待进一步探索。在此，我们提出了一种新型的诱导双靶点重新平衡（IDTR）策略，用于同时纠正cGAS和NF-κB p65的缺陷。通过使用我们的IDTR方法，我们首次表明溶瘤腺病毒H101可以重新激活沉默的cGAS，而沉默GAU1长链非编码RNA（lncRNA）可抑制NF-κB p65的过度激活，从而在结直肠癌中产生高效的体外和体内抗肿瘤疗效。有趣的是，我们进一步证明溶瘤腺病毒通过促进cGAS启动子的H3K4三甲基化来重新激活cGAS。此外，使用反义寡核苷酸沉默GAU1可显著降低NF-κB p65启动子处的H3K27乙酰化，并抑制NF-κB p65转录。我们的研究揭示了cGAS和NF-κB p65这两种肿瘤缺陷背后异常的治疗机制，并提供了一种基于溶瘤腺病毒和反义寡核苷酸的替代IDTR方法，以实现肿瘤的高效治疗效果。
