BACKGROUND
Epithelial-mesenchymal transition (EMT) and glycolysis contribute to breast cancer (BC). However, the molecular mechanisms underlying these processes require further investigation.
METHODS
Gene abundance was determined using RT-qPCR, Western blotting, and IHC. Cell viability and migration were evaluated using CCK-8 and scratch tests. Co-IP was performed to confirm the RNF125-HDAC1 interaction. Glycolysis-related indicators were detected using commercial kits, the Seahorse XF assay, and Western blotting. The enrichment of H3K27ac in the PGM5 promoter was determined using ChIP.
RESULTS
In BC samples, RNF125 and PGM5 levels were downregulated, whereas HDAC1 expression was upregulated. Upregulation of RNF125 inhibited EMT and glycolysis in BC cells, suppressed tumor growth in subcutaneous tumor-bearing mouse models, and reduced lung metastasis in mice; these effects were counteracted by HDAC1 overexpression. Similarly, PGM5 overexpression suppressed EMT and glycolysis in BC cells; however, this suppression was blocked by HDAC1 overexpression or RNF125 knockdown. Mechanistically, RNF125 promoted HDAC1 ubiquitination, leading to its proteasomal degradation. Moreover, HDAC1 reduced PGM5 expression by inhibiting H3K27ac enrichment at the PGM5 promoter.
CONCLUSION
RNF125 suppressed EMT and glycolysis in BC cells and delayed tumor growth in subcutaneous tumor-bearing mouse models, as well as lung metastasis in mice through modulation of the HDAC1/PGM5 axis.
Yanhong Wei, Zhaohui Tang, P. Luo et al.· Epigenomics· 0 citations
Colorectal cancer (CRC) remains a global health challenge with limited efficacy of single-target therapies. Esculin and esculetin, the main coumarins of Cortex Fraxini, have been reported to exhibit anti-tumor activities in various cancer cell lines in preclinical studies. This study systematically elucidated the synergistic anti-CRC mechanisms of esculin and esculetin by integrating network pharmacology, bioinformatics, molecular docking, molecular dynamics simulations, and in vitro validation. Network pharmacology predicted 23 overlapping targets, with 10 core proteins significantly enriched in the PI3K-Akt and JAK2-STAT3 pathways, further supported by bioinformatics analysis. Molecular docking and 100-ns molecular dynamics simulations revealed that the esculin-esculetin complex exhibited stronger binding affinity and stable interaction with EGFR compared with each monomer. In vitro, the natural 5:1 combination synergistically inhibited HCT116 and HT29 cell proliferation, suppressed colony formation, migration, and invasion, downregulated the phosphorylation of PI3K, Akt, JAK2 and STAT3, reduced EGFR, TOP1 and CDK2 mRNA, decreased the Bcl-2/Bax ratio, and increased cleaved caspase-3 levels. Quantitative validation by EdU, TUNEL, and flow cytometry confirmed concentration-dependent inhibition of proliferation and induction of apoptosis. These findings demonstrate that esculin and esculetin co-target EGFR and simultaneously block downstream PI3K-Akt and JAK2-STAT3 dual pathways, providing a multi-component, multi-target, multi-pathway synergistic model for C. fraxini-based combination therapy against CRC.
Lin Liao, Zhaohui Tang, P. Luo et al.· Toxicology and Applied Pharm...· 0 citations