Induced dual-target rebalance simultaneously enhances efficient therapeutical efficacy in tumors
Xiaoyu Zhang1,2,3, Tianyi Ding1,2,3, Fan Yang1,2,3
1State 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.
Abstract:
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.
Insights
This study introduces a new strategy to fix two key cancer-driving gene defects simultaneously. The approach uses oncolytic adenovirus and gene silencing to effectively treat colorectal tumors.
Area of Science:
- Oncology
- Molecular Biology
- Gene Therapy
Background:
- Tumorigenesis is driven by multiple gene abnormalities, including NF-κB p65 overactivation and cGAS silencing.
- Simultaneous correction of these defects presents a therapeutic challenge.
Purpose of the Study:
- To develop and evaluate a novel Induced Dual-Target Rebalance (IDTR) strategy for simultaneously correcting cGAS and NF-κB p65 abnormalities.
- To investigate the underlying molecular mechanisms of the IDTR approach in colorectal tumors.
Main Methods:
- Utilized oncolytic adenovirus H101 to reactivate silenced cGAS.
- Employed antisense oligonucleotides to silence GAU1 long noncoding RNA (lncRNA), inhibiting NF-κB p65 overactivation.
- Assessed in vitro and in vivo antitumor efficacy.
- Investigated epigenetic modifications at the cGAS and NF-κB p65 promoters (H3K4 trimethylation and H3K27 acetylation).
Main Results:
- The IDTR strategy efficiently reactivated cGAS via H3K4 trimethylation of its promoter.
- Silencing GAU1 reduced H3K27 acetylation at the NF-κB p65 promoter, inhibiting its transcription.
- Demonstrated significant in vitro and in vivo antitumor efficacy in colorectal tumors.
Conclusions:
- The IDTR approach offers a novel therapeutic strategy for tumors with cGAS and NF-κB p65 defects.
- Oncolytic adenovirus and antisense oligonucleotides can be combined for efficient tumor treatment.
- Elucidated the epigenetic mechanisms involved in cGAS reactivation and NF-κB p65 inhibition.
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