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Updated: Jul 3, 2025
A Syngeneic Orthotopic Osteosarcoma Sprague Dawley Rat Model with Amputation to Control Metastasis Rate
Published on: May 3, 2021
Revealing the pharmacological effects of Remodelin against osteosarcoma based on network pharmacology, acRIP-seq and
Jia Gao1, Peili Xu1, Feng Wang2
1Department of Orthopedics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, Jiangsu, People's Republic of China.
Abstract:
Osteosarcoma (OS) is the most common primary malignant tumor of bone. Remodelin, an inhibitor of the N (4)-Acetylcytidine (ac4C) acetylation modifying enzyme N-acetyltransferase 10 (NAT10), has been shown to have therapeutic effects on cancer in several studies, and our previous studies have confirmed the inhibitory effect of Remodelin on OS cells, however, the mechanism of action has not yet been elucidated. We used network pharmacological analysis to quantify the therapeutic targets of Remodelin against OS. acRIP-seq and RNA-seq were performed to investigate the inhibitory activity of Remodelin on acetylation and its effect on the transcriptome after intervening in OS cells U2OS with Remodelin in vitro. Key target genes were deduced based on their pharmacological properties, combined with network pharmacology results and sequencing results. Finally, the deduced target genes were validated with vitro experiments. Network pharmacological analysis showed that 2291 OS-related target genes and 369 Remodelin-related target genes were obtained, and 116 overlapping genes were identified as Remodelin targets for OS treatment. Sequencing results showed that a total of 13,736 statistically significant ac4C modification peaks were detected by acRIP-seq, including 6938 hypoacetylation modifications and 6798 hyperacetylation modifications. A total of 2350 statistically significant mRNAs were detected by RNA-seq, of which 830 were up-regulated and 1520 were down-regulated. Association analyses identified a total of 382 genes that were Hypoacetylated-down, consistent with inhibition of mRNA acetylation and expression by Remodelin. Five genes, CASP3, ESR2, FGFR2, IGF1 and MAPK1, were identified as key therapeutic targets of Remodelin against OS. Finally, in vitro experiments, CCK-8 and qRT-PCR demonstrated that Remodelin indeed inhibited the proliferation of OS cells and reduced the expression of three genes: ESR2, IGF1, and MAPK1. In conclusion, ESR2, IGF1 and MAPK1 were identified as key therapeutic targets of Remodelin against OS. This reveals the target of Remodelin's pharmacological action on OS and provides new ideas for the treatment of OS.
Insights
Remodelin inhibits osteosarcoma (OS) cell proliferation by targeting ESR2, IGF1, and MAPK1. This study elucidates Remodelin's mechanism of action against OS, identifying key therapeutic targets for future treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Osteosarcoma (OS) is the most common primary bone cancer.
- Remodelin, an inhibitor of N-acetyltransferase 10 (NAT10), shows therapeutic potential in cancer.
- The precise mechanism of Remodelin's action against OS remains unclear.
Purpose of the Study:
- To identify the therapeutic targets of Remodelin in osteosarcoma using network pharmacology.
- To investigate Remodelin's effect on ac4C acetylation and gene expression in OS cells.
- To validate potential therapeutic targets through in vitro experiments.
Main Methods:
- Network pharmacological analysis to identify overlapping targets of Remodelin and OS.
- acRIP-seq and RNA-seq to analyze changes in ac4C modification and transcriptome.
- In vitro experiments (CCK-8, qRT-PCR) to validate target gene expression and cell proliferation.
Main Results:
- Network pharmacology identified 116 overlapping genes as potential Remodelin targets for OS.
- acRIP-seq and RNA-seq revealed significant alterations in ac4C modifications and mRNA expression.
- Association analysis highlighted 382 hypoacetylated-down genes, with ESR2, IGF1, and MAPK1 identified as key targets.
Conclusions:
- Remodelin inhibits osteosarcoma cell proliferation.
- ESR2, IGF1, and MAPK1 are identified as key therapeutic targets of Remodelin in osteosarcoma.
- This study provides insights into Remodelin's mechanism and potential for OS treatment.
