Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth

Jiajun Zhu, Morgan A. Sammons, Greg Donahue, Zhixun Dou, Masoud Vedadi, Matthaus Getlik, Dalia Barsyte-Lovejoy, Rima Al-Awar, Bryson W. Katona, Ali Shilatifard, Jing Huang, Xianxin Hua, Cheryl H. Arrowsmith, Shelley L. Berger*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

368 Scopus citations

Abstract

TP53 (which encodes p53 protein) is the most frequently mutated gene among all human cancers. Prevalent p53 missense mutations abrogate its tumour suppressive function and lead to a 'gain-of-function' (GOF) that promotes cancer. Here we show that p53 GOF mutants bind to and upregulate chromatin regulatory genes, including the methyltransferases MLL1 (also known as KMT2A), MLL2 (also known as KMT2D), and acetyltransferase MOZ (also known as KAT6A or MYST3), resulting in genome-wide increases of histone methylation and acetylation. Analysis of The Cancer Genome Atlas shows specific upregulation of MLL1, MLL2, and MOZ in p53 GOF patient-derived tumours, but not in wild-type p53 or p53 null tumours. Cancer cell proliferation is markedly lowered by genetic knockdown of MLL1 or by pharmacological inhibition of the MLL1 methyltransferase complex. Our study reveals a novel chromatin mechanism underlying the progression of tumours with GOF p53, and suggests new possibilities for designing combinatorial chromatin-based therapies for treating individual cancers driven by prevalent GOF p53 mutations.

Original languageEnglish (US)
Pages (from-to)206-211
Number of pages6
JournalNature
Volume525
Issue number7568
DOIs
StatePublished - Sep 10 2015

Funding

Acknowledgements We thank M. Tainsky for the LFS cell lines; A. Weller, J. Glover and the Stem Cell and Xenograft Core at the University of Pennsylvania for help with the tumourxenograftexperiments.S.L.B. issupported byNIH grantR01 CA078831. M.A.S. is supported by a Postdoctoral Fellowship from the American Cancer Society. X.H. is supported in part by a pilot grant from ITMAT of the University of Pennsylvania. A.S. is supported by NIH grant R01 GM069905. The Structural Genomics Consortium is a registered charity (number 1097737) that receives funds from AbbVie, Bayer, Boehringer Ingelheim, Genome Canada through the Ontario Genomics Institute (OGI-055), GlaxoSmithKline, Janssen, Lilly Canada, Merck, the Novartis Research Foundation, the Ontario Ministry of Economic Development and Innovation, Pfizer, Takeda, and the Wellcome Trust (092809/Z/10/Z). Funding was also provided to C.H.A. from the Canadian Cancer Society Research Institute.

ASJC Scopus subject areas

  • General

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