Wedelolactone disrupts the interaction of EZH2-EED complex and inhibits PRC2-dependent cancer

Area of Science:

• Epigenetics
• Molecular Biology
• Cancer Research

Background:

• Polycomb repressive complex 2 (PRC2) regulates H3K27me3, crucial for development and cancer.
• PRC2's role in tumorigenesis makes it a key target for epigenetic cancer therapy.
• Natural compounds disrupting the enhancer of zeste homolog 2 (EZH2)-embryonic ectoderm development (EED) interaction within PRC2 are scarce.

Purpose of the Study:

• To screen and identify natural compounds capable of disrupting the EZH2-EED interaction.
• To evaluate the therapeutic potential of identified compounds in PRC2-dependent cancers.

Main Methods:

• Screening of natural compounds for EZH2-EED interaction disruption.
• In vitro assays to determine binding affinity (KD) and interaction blocking.
• Assessment of PRC2 component degradation and downstream gene expression modulation.
• Cell-based assays to observe cancer cell growth arrest.

Main Results:

• Wedelolactone was identified as a potent inhibitor, binding to EED with high affinity (KD = 2.82 μM).
• Wedelolactone effectively blocked the EZH2-EED interaction in vitro.
• Treatment with wedelolactone induced degradation of PRC2 core components.
• Modulation of PRC2 downstream targets and cancer-related genes was observed.
• Wedelolactone induced growth arrest in PRC2-dependent cancer cells.

Conclusions:

• Wedelolactone disrupts the EZH2-EED interaction, leading to PRC2 complex destabilization.
• Wedelolactone shows promise as a therapeutic agent for PRC2-dependent cancers.
• Wedelolactone derivatives targeting the EZH2-EED interaction warrant further investigation for cancer treatment.