Journal
EMBO JOURNAL
Volume 38, Issue 5, Pages -Publisher
WILEY
DOI: 10.15252/embj.201899599
Keywords
EZH2; gain-of-function mutation; metastasis; non-methyltransferase activity; p53
Categories
Funding
- National Institutes of Health [CA134514, CA130908, CA193239, CA203849]
- Mayo Clinic Center for Individualized Medicine
- Kendall Fellowship in Biochemistry Award
- Department of Defense [W81XWH-09-1-622, W81XWH-14-1-0486, W81XWH-17-1-0415]
- Pacific Northwest SPORE in Prostate Cancer [P50CA097186]
- Prostate Cancer Foundation
Ask authors/readers for more resources
In light of the increasing number of identified cancer-driven gain-of-function (GOF) mutants of p53, it is important to define a common mechanism to systematically target several mutants, rather than developing strategies tailored to inhibit each mutant individually. Here, using RNA immunoprecipitation-sequencing (RIP-seq), we identified the Polycomb-group histone methyltransferase EZH2 as a p53 mRNA-binding protein. EZH2 bound to an internal ribosome entry site (IRES) in the 5UTR of p53 mRNA and enhanced p53 protein translation in a methyltransferase-independent manner. EZH2 augmented p53 GOF mutant-mediated cancer growth and metastasis by increasing protein levels of mutant p53. EZH2 overexpression was associated with worsened outcome selectively in patients with p53-mutated cancer. Depletion of EZH2 by antisense oligonucleotides inhibited p53 GOF mutant-mediated cancer growth. Our findings reveal a non-methyltransferase function of EZH2 that controls protein translation of p53 GOF mutants, inhibition of which causes synthetic lethality in cancer cells expressing p53 GOF mutants.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available