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Nature. 2015 Sep 10;525(7568):206-11. doi: 10.1038/nature15251. Epub 2015 Sep 2.

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

Author information

1
Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
2
Epigenetics Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
3
Biomedical Graduate Studies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
4
Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
5
Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
6
Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
7
Abramson Family Cancer Research Institute, Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
8
Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, 320 E. Superior Street, Chicago, Illinois 60611, USA.
9
Cancer and Stem Cell Epigenetics, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
10
Princess Margaret Cancer Centre, and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2C4, Canada.

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.

PMID:
26331536
PMCID:
PMC4568559
DOI:
10.1038/nature15251
[Indexed for MEDLINE]
Free PMC Article

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