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

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 5'UTR 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.

Source: EMBO Journal - March 1, 2019 Category: Molecular Biology Authors: Zhao, Y., Ding, L., Wang, D., Ye, Z., He, Y., Ma, L., Zhu, R., Pan, Y., Wu, Q., Pang, K., Hou, X., Weroha, S. J., Han, C., Coleman, R., Coleman, I., Karnes, R. J., Zhang, J., Nelson, P. S., Wang, L., Huang, H. Tags: Cancer, Molecular Biology of Disease, Protein Biosynthesis & Quality Control Articles Source Type: research