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

Yu Zhao, Liya Ding, Dejie Wang, Zhenqing Ye, Yundong He, Linlin Ma, Runzhi Zhu, Yunqian Pan, Qiang Wu, Kun Pang, Xiaonan Hou, Saravut (John) Weroha, Conghui Han, Roger Coleman, Ilsa Coleman, Robert Jeffrey Karnes, Jun Zhang, Peter S. Nelson, Liguo Wang, Haojie Huang

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere99599
JournalEMBO Journal
DOIs
StatePublished - Jan 1 2019

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Neoplasm Metastasis
Growth
Protein Biosynthesis
Neoplasms
RNA Sequence Analysis
Messenger RNA
Antisense Oligonucleotides
Methyltransferases
Mutant Proteins
Proteins
Immunoprecipitation
Carrier Proteins
Cells
RNA

Keywords

  • EZH2
  • gain-of-function mutation
  • metastasis
  • non-methyltransferase activity
  • p53

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

EZH2 cooperates with gain-of-function p53 mutants to promote cancer growth and metastasis. / Zhao, Yu; Ding, Liya; Wang, Dejie; Ye, Zhenqing; He, Yundong; Ma, Linlin; Zhu, Runzhi; Pan, Yunqian; Wu, Qiang; Pang, Kun; Hou, Xiaonan; Weroha, Saravut (John); Han, Conghui; Coleman, Roger; Coleman, Ilsa; Karnes, Robert Jeffrey; Zhang, Jun; Nelson, Peter S.; Wang, Liguo; Huang, Haojie.

In: EMBO Journal, 01.01.2019.

Research output: Contribution to journalArticle

Zhao, Y, Ding, L, Wang, D, Ye, Z, He, Y, Ma, L, Zhu, R, Pan, Y, Wu, Q, Pang, K, Hou, X, Weroha, SJ, Han, C, Coleman, R, Coleman, I, Karnes, RJ, Zhang, J, Nelson, PS, Wang, L & Huang, H 2019, 'EZH2 cooperates with gain-of-function p53 mutants to promote cancer growth and metastasis', EMBO Journal. https://doi.org/10.15252/embj.201899599
Zhao, Yu ; Ding, Liya ; Wang, Dejie ; Ye, Zhenqing ; He, Yundong ; Ma, Linlin ; Zhu, Runzhi ; Pan, Yunqian ; Wu, Qiang ; Pang, Kun ; Hou, Xiaonan ; Weroha, Saravut (John) ; Han, Conghui ; Coleman, Roger ; Coleman, Ilsa ; Karnes, Robert Jeffrey ; Zhang, Jun ; Nelson, Peter S. ; Wang, Liguo ; Huang, Haojie. / EZH2 cooperates with gain-of-function p53 mutants to promote cancer growth and metastasis. In: EMBO Journal. 2019.
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AU - Ding, Liya

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AU - Ma, Linlin

AU - Zhu, Runzhi

AU - Pan, Yunqian

AU - Wu, Qiang

AU - Pang, Kun

AU - Hou, Xiaonan

AU - Weroha, Saravut (John)

AU - Han, Conghui

AU - Coleman, Roger

AU - Coleman, Ilsa

AU - Karnes, Robert Jeffrey

AU - Zhang, Jun

AU - Nelson, Peter S.

AU - Wang, Liguo

AU - Huang, Haojie

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AB - 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.

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