@article{f9c56ba241b5456f83c8d6b3ac9d4297,
title = "EZH2 cooperates with gain-of-function p53 mutants to promote cancer growth and metastasis",
abstract = "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.",
keywords = "EZH2, gain-of-function mutation, metastasis, non-methyltransferase activity, p53",
author = "Yu Zhao and Liya Ding and Dejie Wang and Zhenqing Ye and Yundong He and Linlin Ma and Runzhi Zhu and Yunqian Pan and Qiang Wu and Kun Pang and Xiaonan Hou and Weroha, {Saravut J.} and Conghui Han and Roger Coleman and Ilsa Coleman and Karnes, {R. Jeffery} and Jun Zhang and Nelson, {Peter S.} and Liguo Wang and Haojie Huang",
note = "Funding Information: We thank the patients and their families for their altruism in participating in research studies. We also thank Xinbin Chen, Qiang Yu, Zhenbang Chen, and Da-Qing Yang for reagents and suggestions; Wenqian Hu from Mayo Clinic for providing facilities for polysome fractionation; Youngsoo Kim and Robert MacLeod from Ionis Pharmaceuticals Inc for providing EZH2 ASOs; members of Huang laboratory for their constructive comments for the study; Colm Morris-sey, Robert Vessella, Larry True, Xiaotun Zhang, and all other members of the University of Washington rapid autopsy team for their tremendous efforts. This work was supported in part by grants from the National Institutes of Health (CA134514, CA130908, CA193239, and CA203849 to H.H.), the Mayo Clinic Center for Individualized Medicine (to H.H.), the Kendall Fellowship in Biochemistry Award (to Y.Z.), the Department of Defense (W81XWH-09-1-622 and W81XWH-14-1-0486 to H.H. and W81XWH-17-1-0415 to P.S.N.), the Pacific Northwest SPORE in Prostate Cancer P50CA097186 (to P.S.N.), and the Prostate Cancer Foundation (to P.S.N.).",
year = "2019",
month = mar,
day = "1",
doi = "10.15252/embj.201899599",
language = "English (US)",
volume = "38",
journal = "EMBO Journal",
issn = "0261-4189",
publisher = "Nature Publishing Group",
number = "5",
}