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

## TL;DR

This study reveals how two proteins, HIF-1α and EZH2, interact in lung cancer and introduces a new drug that targets both to overcome resistance and inhibit tumor growth.

## Contribution

The study identifies a negative feedback loop between HIF-1α and EZH2 and introduces a dual-target compound, DYB-03, for effective lung cancer therapy.

## Key findings

- EZH2 mediates resistance to HIF-1 inhibitors by enhancing its activity through SUZ12 transcription.
- DYB-03 effectively inhibits both HIF-1α and EZH2, reducing cancer cell migration, invasion, and angiogenesis.
- DYB-03 reverses resistance to existing inhibitors and shows strong antitumor activity in xenograft models.

## 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.

The negative feedback regulation between EZH2 and HIF‐1α is identified and confirmed in vitro and in vivo, which mediates multidrug resistance to HIF‐1 inhibitor and EZH2 inhibitor. DYB‐03 is a newly screened dual‐target compound that targeting both HIF‐1α and EZH2 and displays significant anti‐tumor activity in vitro and in vivo, indicating the potential for clinical combination target therapy.