# A Small-Molecule Compound Targeting Canine Mammary Cancer Regulates CXCL10 and MECOM Transcripts via Histone Modifications in CMT-N7

## TL;DR

This study shows that two new drugs, W6134 and XY018, may help treat canine mammary cancer by altering gene activity through changes in histone proteins.

## Contribution

The study identifies RORγ inhibitors W6134 and XY018 as novel modulators of inflammatory pathways in canine mammary cancer via histone modifications.

## Key findings

- W6134 and XY018 upregulate apoptosis and inflammatory signaling pathways in CMT-N7 cells.
- The drugs alter expression of CXCL10 and MECOM genes through histone modifications like H3K27ac and H3K4me1.
- RORγ is confirmed as a potential therapeutic target for canine mammary cancer.

## Abstract

This study aims to explore the potential therapeutic effects of two novel drugs, W6134 and XY018, on canine mammary cancer cells, while providing new targets for the treatment of canine mammary cancer. This work focused on the molecular mechanisms by which these two drugs inhibit cancer cell growth, particularly through histone modifications to regulate the inflammatory genes CXCL10 and MECOM. The finding revealed that treatment with W6134 and XY018 upregulates apoptosis, cellular inflammatory signaling pathways, and alters the expression of related genes, providing a new perspective for the treatment of canine mammary cancer. Overall, our study provides molecular evidence that W6134 and XY018 may inhibit canine cancer cells by modulating inflammatory pathways.

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.