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Genkwanin impairs triple-negative breast cancer aggressiveness and metastasis by targeting Lysine Demethylase 4C
Hanfeng Xu1, Jie Gao1, Shiyong Fu1
1Department of Oncology, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine. Nanjing, 210003, PR China.
Background:
Triple-negative breast cancer, the most aggressive breast cancer with highest metastatic capacity and the worst prognosis, accounts for 15 % of breast cancer. According to prior studies, the natural active component genkwanin suppressed cell growth in estrogen-receptor-positive breast cancer. Nonetheless, its impact on triple-negative breast cancer and its target remains poorly understood.
Purpose:
To explore the effects of genkwanin and identify the direct targets and cellular mechanism of genkwanin in triple-negative breast cancer.
Study Design:
The effects of genkwanin were investigated in SUM-159PT and MDA-MB-231 cells. Direct target protein of genkwanin were identified by Quantitative proteomics. The in-vivo effect of genkwanin on triple-negative breast cancer was investigated using mouse models.
Methods:
The anti-metastasis effects of genkwanin were investigated by individual cell-tracking assay and 3D-on top assay. Quantitative proteomics was used to identify the target of genkwanin and microscale thermophoresis ligand-binding assay was performed to further confirmed it. In-vitro and in-vivo extreme limiting diluting assays were performed to investigate the inhibitory effect of stemness. Lung metastasis mouse model was used to evaluate the anti-metastasis effects of genkwanin.
Results:
This study demonstrated that genkwanin could significantly attenuate migration and invasion in triple-negative breast cancer cells. Notably, genkwanin could efficiently modulate the stemness of breast cancer cells and improve its sensitivity to paclitaxel (PTX). Lysine demethylase 4C (KDM4C) was identified as the target of genkwanin and the in-vivo therapeutic effect of genkwanin was also confirmed in 4T1-luc lung metastasis model. Mechanically, genkwanin reduced KDM4C expression, which regulated the lysine demethylation of histone H3, thereby suppressing KLF14 transcription. KLF14 acts as a switch of lipid synthesis and regulates intracellular cholesterol levels, inhibiting cancer metastasis.
Conclusion:
These results demonstrate genkwanin's therapeutic potential in triple-negative breast cancer and its effect on targeting metastasis.
Insights
Genkwanin, a natural compound, effectively inhibits triple-negative breast cancer (TNBC) metastasis by targeting KDM4C and modulating cancer stemness. This study reveals genkwanin
Area of Science:
- Biochemistry
- Oncology
- Pharmacology
Background:
- Triple-negative breast cancer (TNBC) is aggressive with poor prognosis, accounting for 15% of breast cancers.
- Genkwanin has shown growth suppression in estrogen-receptor-positive breast cancer, but its TNBC effects and targets were unknown.
Purpose of the Study:
- To investigate genkwanin's effects on TNBC.
- To identify genkwanin's direct targets and cellular mechanisms in TNBC.
Main Methods:
- Genkwanin's effects were tested on SUM-159PT and MDA-MB-231 TNBC cells.
- Quantitative proteomics identified genkwanin's protein targets, confirmed by microscale thermophoresis.
- In vivo studies used mouse models to assess anti-metastasis and stemness-inhibitory effects.
Main Results:
- Genkwanin significantly reduced migration and invasion in TNBC cells.
- Genkwanin modulated cancer stemness and enhanced sensitivity to paclitaxel (PTX).
- Lysine demethylase 4C (KDM4C) was identified as a direct target, with genkwanin reducing KDM4C expression, suppressing KLF14 transcription, and inhibiting metastasis.
Conclusions:
- Genkwanin demonstrates therapeutic potential for TNBC.
- Genkwanin effectively targets metastasis in TNBC by inhibiting the KDM4C/KLF14 pathway.
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