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 language | English (US) |
|---|---|
| Article number | e99599 |
| Journal | EMBO Journal |
| DOIs | |
| State | Published - Jan 1 2019 |
Fingerprint
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 journal › Article
}
TY - JOUR
T1 - EZH2 cooperates with gain-of-function p53 mutants to promote cancer growth and metastasis
AU - Zhao, Yu
AU - Ding, Liya
AU - Wang, Dejie
AU - Ye, Zhenqing
AU - He, Yundong
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
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
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.
KW - EZH2
KW - gain-of-function mutation
KW - metastasis
KW - non-methyltransferase activity
KW - p53
UR - http://www.scopus.com/inward/record.url?scp=85061062611&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85061062611&partnerID=8YFLogxK
U2 - 10.15252/embj.201899599
DO - 10.15252/embj.201899599
M3 - Article
C2 - 30723117
AN - SCOPUS:85061062611
JO - EMBO Journal
JF - EMBO Journal
SN - 0261-4189
M1 - e99599
ER -