Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth
Open accessAbstract
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.
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RNA expression in mut-p53 glioblastoma tumors showed upregulation of MLL1, MLL2 and MOZ compared to TP53 wild type or null tumors.
“The examination of RNA expression in mut-p53 GBM tumors showed upregulation of MLL1, MLL2 and MOZ compared to TP53 wild type or null tumors.”
From The p53 Pathway in Glioblastoma (2018) · cites this paper as [111]
The ‘COMPASS inhibitors reduce GOF p53 cell growth’ section reports higher RNA expression of MLL1, MLL2 and MOZ in GOF-p53 tumors than in wild-type or p53-null tumors. But the analysis pooled several cancer types; Extended Data Figure 9 identifies brain lower-grade glioma, not glioblastoma, among the individually examined types. The cited paper therefore does not establish the claim specifically for GBM tumors (page numbers unavailable in our copy). (LLM, conf=0.88)
Experimental — accuracy not yet measuredGOF mut-p53 binds ETS2 for activation of chromatin remodeler genes such as MLL1, MLL2 and MOZ.
“The analysis determined that GOF mut-p53 binds ETS2 for activation of chromatin remodeler genes such as MLL1, MLL2 (both H3K4 methyltransferases) and MOZ (an acetyltransferase).”
From The p53 Pathway in Glioblastoma (2018) · cites this paper as [111]
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- Authors
- Zhu, J., Sammons, M. A., Donahue, G., Dou, Z., Vedadi, M., Getlik, M., Barsyte-Lovejoy, D., Al-awar, R., Katona, B. W., Shilatifard, A., Huang, J., Hua, X., Arrowsmith, C. H., & Berger, S. L.
- Affiliations
- University of Pennsylvania (US)
- University of Toronto (CA)
- Ontario Institute for Cancer Research (CA)
- Northwestern University (US)
- National Cancer Institute (US)
- Corresponding author
- Berger, Shelley L.
- ORCID
- Venue
- Nature
- Published
- 2015-09-02
- Volume
- 525
- Issue
- 7568
- Pages
- 206-211
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4568559
- OpenAlex
- W1768917741
- Cited by
- 493
- References
- 43
- Citations by year
- 2026: 19 · 2025: 36 · 2024: 36 · 2023: 41 · 2022: 39 · 2021: 42 · 2020: 46 · 2019: 56 · 2018: 49 · 2017: 62 · 2016: 61 · 2015: 6
- FWCI
- 25.87
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Wellcome Trust (092809/Z/10/Z)
- National Cancer Institute (R01CA078831, P30CA060553)
- National Institute of General Medical Sciences (R01GM069905)
- National Institute of Environmental Health Sciences (P30ES013508)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- TP53, MLL1, KMT2D, MOZ, histone methyltransferase, histone acetylation, chromatin modification, cancer therapy, tumor growth
- MeSH terms
- Acetylation, Animals, Chromatin, Female, Histones, Humans, Male, Mutation, Neoplasms, Phenotype, Protein Binding, Histone-Lysine N-Methyltransferase, Protein Processing, Post-Translational, Genome, Human, Genes, Tumor Suppressor, Tumor Suppressor Protein p53, Cell Line, Tumor, Cell Proliferation, Mutant Proteins, Mice, Histone Acetyltransferases, Myeloid-Lymphoid Leukemia Protein
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