EZH2 cooperates with gain-of-function p53 mutants to promote cancer growth and metastasis

Area of Science:

• Oncology
• Molecular Biology
• Epigenetics

Background:

• Increasing identification of cancer-driving gain-of-function (GOF) p53 mutants necessitates unified targeting strategies.
• Targeting individual p53 mutants is less efficient than a common mechanism approach.

Purpose of the Study:

• To identify a common mechanism to target multiple p53 GOF mutants.
• To investigate the role of EZH2 in regulating p53 protein translation and cancer progression.

Main Methods:

• RNA immunoprecipitation-sequencing (RIP-seq) to identify p53 mRNA-binding proteins.
• Assessing EZH2's effect on p53 protein translation and cancer growth.
• Analyzing EZH2 expression in patient data.

Main Results:

• EZH2 was identified as a p53 mRNA-binding protein, interacting with an IRES in the 5'UTR.
• EZH2 enhances p53 protein translation independently of its methyltransferase activity.
• EZH2 overexpression correlates with poor outcomes in p53-mutated cancer patients.
• EZH2 depletion inhibits p53 GOF mutant-driven cancer growth and metastasis.

Conclusions:

• EZH2 possesses a non-methyltransferase function controlling p53 GOF mutant translation.
• Inhibiting EZH2 induces synthetic lethality in cancers with p53 GOF mutants.
• Targeting EZH2 offers a novel therapeutic strategy for p53-mutated cancers.