A covalently bound inhibitor triggers EZH2 degradation through CHIP-mediated ubiquitination

Area of Science:

• Oncology
• Molecular Biology
• Epigenetics

Background:

• Enhancer of zeste homolog 2 (EZH2) is a key oncogene and drug target in cancers.
• Existing EZH2 inhibitors primarily target its enzymatic function, but EZH2 has other oncogenic roles.
• A comprehensive suppression of all EZH2 functions is necessary for effective cancer therapy.

Purpose of the Study:

• To identify a novel therapeutic strategy targeting EZH2 beyond its enzymatic activity.
• To investigate a new class of EZH2 inhibitors based on gambogenic acid (GNA) derivatives.
• To explore the mechanism of GNA-induced EZH2 degradation and its anti-cancer effects.

Main Methods:

• Identification of a GNA derivative that covalently binds to Cys668 in the EZH2-SET domain.
• Investigation of EZH2 degradation via COOH terminus of Hsp70-interacting protein (CHIP)-mediated ubiquitination.
• Assessment of inhibitor efficacy in suppressing H3K27Me3, reactivating tumor suppressor genes, and inhibiting tumor growth in vivo.

Main Results:

• The novel GNA derivative specifically targets and binds to Cys668 of EZH2.
• This binding triggers EZH2 degradation through CHIP-mediated ubiquitination.
• Inhibitors suppressed H3K27Me3, reactivated silenced tumor suppressor genes, and reduced tumor growth.
• Tumors with a C668S-EZH2 mutation showed resistance, confirming EZH2 dependency.

Conclusions:

• GNA derivatives represent a unique strategy for targeting EZH2 by inducing its degradation.
• This approach effectively inhibits oncogenic functions of EZH2, including PRC2-independent roles.
• Targeting the GNA-mediated EZH2 destruction pathway offers a promising new avenue for anti-cancer drug development.