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The Regulation of Hypoxia Inducible Factor (HIF)1α Expression by Quercetin: an In Silico Study
Sri Puji Astuti Wahyuningsih1, Firli Rahmah Primula Dewi1, Amy Saik Yi Hsan2
1Department of Biology, Faculty of Science and Technology, Universitas Airlangga, Surabaya, Indonesia.
Background:
Cancer disease is a growing health problem in developing and developed countries. Hypoxia-inducible factor-1a (HIF1α) is a transcription factor responsible for expressing several proteins involved in angiogenesis. Quercetin can suppress HIF1α expression due to the inhibition of protein synthesis. However, to date, the study exploring the potential of quercetin in repressing HIF1α through its degradation mechanism has never been done. An in silico study is needed as a preliminary study to understand the mechanism underlining this possibility.
Objective:
This study aimed to investigate the potential of quercetin in regulating HIF1α expression through the ubiquitin degradation pathway by in silico study.
Methods:
This study was performed by in silico analysis, including biological activity prediction, 3D protein structure collection, protein-ligand and protein-protein docking, and the visualization of the docking results.
Results:
The probability activity (Pa) score of quercetin as an HIF1α expression inhibitor was 0.969. In the absence of quercetin, the center-weighted score of HIF1α - pVHL, HIF1α - FIH, and HIF1α - PHD2 was -699.4 kJ/mol, -846.0 kJ/mol, and -650.5 kJ/mol, respectively. In the presence of quercetin, the weighted score of HIF1α - pVHL, HIF1α - FIH, and HIF1α - PHD2 was reduced to -728.1 kJ/mol, -854.2 kJ/mol, and -650.5 kJ/mol, respectively.
Conclusion:
Quercetin could directly promote HIF1α and pVHL interaction, thus increasing the degradation of HIF1α by ubiquitin-dependent pathway.
Insights
Quercetin may inhibit cancer by promoting the degradation of Hypoxia-inducible factor-1a (HIF1α) through the ubiquitin pathway. This in silico study suggests quercetin enhances HIF1α and pVHL interaction, leading to increased HIF1α breakdown.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Cancer disease is a significant global health concern.
- Hypoxia-inducible factor-1a (HIF1α) is a key transcription factor in angiogenesis, crucial for tumor growth.
- Quercetin is known to suppress HIF1α expression via protein synthesis inhibition, but its role in degradation pathways is unexplored.
Purpose of the Study:
- To investigate the potential of quercetin in regulating HIF1α expression through the ubiquitin degradation pathway.
- To conduct a preliminary in silico study to elucidate the mechanism of quercetin's action on HIF1α degradation.
Main Methods:
- In silico analysis was employed, including biological activity prediction.
- 3D protein structures were collected for docking simulations.
- Protein-ligand and protein-protein docking were performed, followed by visualization of results.
Main Results:
- Quercetin demonstrated a high probability of activity (Pa score 0.969) as an HIF1α inhibitor.
- Docking analysis revealed that quercetin binding reduced the weighted scores for HIF1α interactions with pVHL, FIH, and PHD2.
- Specifically, quercetin enhanced the interaction between HIF1α and pVHL.
Conclusions:
- Quercetin shows potential in targeting HIF1α degradation via the ubiquitin-dependent pathway.
- The findings suggest quercetin directly promotes HIF1α and pVHL interaction, facilitating HIF1α degradation.
- This study provides a mechanistic basis for quercetin's anti-cancer effects through HIF1α regulation.
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