Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth.
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.
Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Epigenetics Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Biomedical Graduate Studies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Jiajun
J
Zhu
Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Epigenetics Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Morgan A
MA
Sammons
Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Epigenetics Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Greg
G
Donahue
Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Epigenetics Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Zhixun
Z
Dou
Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.|Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Masoud
M
Vedadi
Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
Matthäus
M
Getlik
Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
Dalia
D
Barsyte-Lovejoy
Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.|Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
Rima
R
Al-awar
Abramson Family Cancer Research Institute, Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Bryson W
BW
Katona
Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, 320 E. Superior Street, Chicago, Illinois 60611, USA.
Ali
A
Shilatifard
Cancer and Stem Cell Epigenetics, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
Jing
J
Huang
Abramson Family Cancer Research Institute, Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Xianxin
X
Hua
Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.|Princess Margaret Cancer Centre, and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2C4, Canada.
Cheryl H
CH
Arrowsmith
Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Epigenetics Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Shelley L
SL
Berger
D000107:Acetylation; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002843:Chromatin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D016147:Genes, Tumor Suppressor; D015894:Genome, Human / Q000235:genetics; D051548:Histone Acetyltransferases / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*
D002843:Chromatin; D006657:Histones; C497422:KMT2A protein, human; D050505:Mutant Proteins; D016159:Tumor Suppressor Protein p53; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; D051548:Histone Acetyltransferases; C108712:KAT6A protein, human