The Interplay Between HIF‐1α and EZH2 in Lung Cancer and Dual‐Targeted Drug Therapy

Autor: Jianmin Wang, Cheng Yang, Huashen Xu, Xinyu Fan, Lina Jia, Yang Du, Shougeng Liu, Wenjing Wang, Jie Zhang, Yu Zhang, Xiaoxue Wang, Zhongbo Liu, Jie Bao, Songping Li, Jingyu Yang, Chunfu Wu, Jing Tang, Guoliang Chen, Lihui Wang
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: Advanced Science, Vol 11, Iss 7, Pp n/a-n/a (2024)
Druh dokumentu: article
ISSN: 2198-3844
DOI: 10.1002/advs.202303904
Popis: Abstract 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.
Databáze: Directory of Open Access Journals
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