The Interplay Between HIF-1α and EZH2 in Lung Cancer and Dual-Targeted Drug Therapy.
Jianmin WangCheng YangHuashen XuXinyu FanLina JiaYang DuShougeng LiuWenjing WangJie ZhangYu ZhangXiaoxue WangZhongbo LiuJie BaoSongping LiJingyu YangChunfu WuJing TangGuoliang ChenLihui WangPublished in: Advanced science (Weinheim, Baden-Wurttemberg, Germany) (2023)
Interactions between oncogenic proteins contribute to the phenotype and drug resistance. Here, EZH2 (enhancer of zest homolog 2) is identified as a crucial factor that mediates HIF-1 (hypoxia-inducible factor) inhibitor resistance. Mechanistically, targeting HIF-1 enhanced the activity of EZH2 through transcription activation of SUZ12 (suppressor of zest 12 protein homolog). Conversely, inhibiting EZH2 increased HIF-1α transcription, but not the transcription of other HIF family members. Additionally, the negative feedback regulation between EZH2 and HIF-1α is confirmed in lung cancer patient tissues and a database of cell lines. Moreover, molecular prediction showed that a newly screened dual-target compound, DYB-03, forms multiple hydrogen bonds with HIF-1α and EZH2 to effectively inhibit the activity of both targets. Subsequent studies revealed that DYB-03 could better inhibit migration, invasion, and angiogenesis of lung cancer cells and HUVECs in vitro and in vivo compared to single agent. DYB-03 showed promising antitumor activity in a xenograft tumor model by promoting apoptosis and inhibiting angiogenesis, which could be almost abolished by the deletion of HIF-1α and EZH2. Notably, DYB-03 could reverse 2-ME2 and GSK126-resistance in lung cancer. These findings clarified the molecular mechanism of cross-regulation of HIF-1α and EZH2, and the potential of DYB-03 for clinical combination target therapy.
Keyphrases
- endothelial cells
- long noncoding rna
- long non coding rna
- transcription factor
- signaling pathway
- oxidative stress
- stem cells
- gene expression
- vascular endothelial growth factor
- risk assessment
- mesenchymal stem cells
- drug delivery
- endoplasmic reticulum stress
- single cell
- human health
- bone marrow
- electronic health record