A Small-Molecule Compound Targeting Canine Mammary Cancer Regulates CXCL10 and MECOM Transcripts via Histone
Rongrong Wang1,2, Chuyang Zhu3, Xiaoyue Yuan3
1MOE Joint International Research Laboratory of Animal Health and Food Safety and Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China.
Abstract:
Nuclear receptors are involved in multiple biological processes, among which RORγ can regulate the expression of inflammation-related genes and is thus frequently used as a therapeutic target for cancer. Canine mammary cancer is one of the most common tumor diseases in dogs, with a relative incidence rate of 46.71% for CMT in China over the past five years, severely threatening the life and health of dogs. Therefore, the search for novel drugs targeting canine mammary cancer is of great significance. This study aims to investigate how the RORγ inhibitors W6134 and XY018 affect the expression of inflammatory genes through histone modifications in CMT-N7 cells. These results show that W6134 and XY018 can upregulate signaling pathways related to inflammation and apoptosis and influence the expression of associated genes. The close link between RORγ and inflammation-related genes further confirms that RORγ may serve as a therapeutic target for canine cancer. Additionally, ChIP-qPCR was used to detect the enrichment of histone markers such as P300, H3K27ac, H3K4me1, H3K9la, and H3K9bhb at the target loci of CXCL10 and MECOM genes. Collectively, our findings provide molecular evidence for the protective role of RORγ in canine mammary cancer, potentially by regulating inflammatory pathways via histone modifications, offering new insights for improving the cure rate and survival of affected dogs.
Insights
RORγ inhibitors W6134 and XY018 upregulate inflammation and apoptosis pathways in canine mammary cancer cells. These findings highlight RORγ as a potential therapeutic target for canine cancer by influencing gene expression via histone modifications.
Area of Science:
- Molecular Biology
- Oncology
- Veterinary Medicine
Background:
- Nuclear receptors, including RORγ, regulate inflammation-related genes and are cancer therapeutic targets.
- Canine mammary cancer (CMT) is a prevalent and life-threatening disease in dogs, necessitating novel therapeutic strategies.
- RORγ's role in inflammation suggests its potential as a target for CMT treatment.
Purpose of the Study:
- To investigate the effects of RORγ inhibitors W6134 and XY018 on inflammatory gene expression in canine mammary cancer cells (CMT-N7).
- To explore the role of histone modifications in mediating the effects of RORγ inhibitors on gene expression.
- To provide molecular evidence for RORγ as a therapeutic target in canine mammary cancer.
Main Methods:
- Treatment of CMT-N7 cells with RORγ inhibitors W6134 and XY018.
- Analysis of signaling pathways related to inflammation and apoptosis.
- Chromatin immunoprecipitation followed by quantitative PCR (ChIP-qPCR) to detect histone marker enrichment at target gene loci (CXCL10, MECOM).
Main Results:
- W6134 and XY018 treatment upregulated inflammation and apoptosis signaling pathways.
- Histone modifications (P300, H3K27ac, H3K4me1, H3K9la, H3K9bhb) were detected at CXCL10 and MECOM gene loci.
- RORγ inhibition influenced the expression of associated inflammatory genes.
Conclusions:
- RORγ plays a protective role in canine mammary cancer, potentially through regulating inflammatory pathways via histone modifications.
- RORγ inhibitors W6134 and XY018 demonstrate potential as therapeutic agents for canine mammary cancer.
- These findings offer new insights for improving treatment outcomes and survival rates in dogs with mammary cancer.
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