EZH2 co-opts gain-of-function p53 mutants to promote cancer growth and metastasis

Zhao, Y.; Ding, L.; Wang, D.; Ye, Z.; Pan, Y.; Ma, L.; Coleman, R.; Coleman, I.; Karnes, R. J.; Zhang, J.; Nelson, P. S.; Wang, L.; Zhu, R.; Huang, H.

doi:10.1101/298737

bioRxiv · 10.1101/298737

EZH2 co-opts gain-of-function p53 mutants to promote cancer growth and metastasis

Zhao, Y.·Ding, L.·Wang, D.·Ye, Z.·Pan, Y.·Ma, L.·Coleman, R.·Coleman, I.·Karnes, R. J.·Zhang, J.·Nelson, P. S.·Wang, L.·Zhu, R.·Huang, H.

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Abstract

With the unfolding of more and more cancer-driven gain-of-function (GOF) mutants of p53, it is important to define a common mechanism to systematically target different mutants rather than develop strategies tailored to inhibit each mutant individually. Here, using RNA immunoprecipitation sequencing (RIP-seq) we identified EZH2 as a p53 mRNA-binding protein. EZH2 bound to the internal ribosome entry site (IRES) in the 5 untranslated region (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 p53 GOF mutant protein level. EZH2 overexpression associated with the worse outcome only 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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Zhao, Y., Ding, L., Wang, D., Ye, Z., Pan, Y., Ma, L., Coleman, R., Coleman, I., Karnes, R. J., Zhang, J., Nelson, P. S., Wang, L., Zhu, R., Huang, H.. 2018-04-10. EZH2 co-opts gain-of-function p53 mutants to promote cancer growth and metastasis. https://doi.org/10.1101/298737

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