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  3. The Interplay Between HIF-1α and EZH2 in Lung Cancer and Dual-Targeted Drug Therapy

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

  • Adv Sci (Weinh). 2024 Feb;11(7):e2303904. doi: 10.1002/advs.202303904.
Jianmin Wang 1 2,  Cheng Yang 1 2,  Huashen Xu 3,  Xinyu Fan 4,  Lina Jia 1 2,  Yang Du 3,  Shougeng Liu 1 2,  Wenjing Wang 1 2,  Jie Zhang 1 2,  Yu Zhang 1 2,  Xiaoxue Wang 1 2,  Zhongbo Liu 5,  Jie Bao 6,  Songping Li 1,  Jingyu Yang 1 2,  Chunfu Wu 1 2,  Jing Tang 6,  Guoliang Chen 3,  Lihui Wang 1 2
Affiliations

Affiliations

  • 1 School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, 110016, P. R. China.
  • 2 Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Benxi, 117004, P. R. China.
  • 3 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, P. R. China.
  • 4 Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, 110004, P. R. China.
  • 5 School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, P. R. China.
  • 6 Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Helsinki, 00290, Finland.
PMID: 38072662 DOI: 10.1002/advs.202303904
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.

Keywords

EZH2; HIF-1α; dual-targeted drugs; feedback regulation; lung cancer.

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