Key Points
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Recurrent somatic mutations of genes encoding chromatin modifiers are among the most prevalent genetic events in cancer.
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Broad epigenetic dysregulation is now understood to be a major enabling characteristic of tumour cells.
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Validated chemical probes enable specific dissection of the molecular processes regulating gene expression at the chromatin interface.
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By combining informative chemical probes with genetic experiments the cancer epigenome can be interrogated to identify new druggable vulnerabilities.
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Emerging epigenetic therapies targeting DNA methylation, post-translational histone modifications and bromodomain-containing reader proteins are rapidly progressing through clinical trials and in some cases have proven efficacy in chemorefractory tumours.
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Preclinical mechanistic data derived from chemical probes provide an important tool for deploying new epigenetically targeted drugs in rational combinations with existing therapeutics while enriching for patient disease groups who are most likely to benefit.
Abstract
Cancer cell hallmarks are underpinned by transcriptional programmes operating in the context of a dynamic and complicit epigenomic environment. Somatic alterations of chromatin modifiers are among the most prevalent cancer perturbations. There is a pressing need for targeted chemical probes to dissect these complex, interconnected gene regulatory circuits. Validated chemical probes empower mechanistic research while providing the pharmacological proof of concept that is required to translate drug-like derivatives into therapy for cancer patients. In this Review, we describe chemical probe development for epigenomic effector proteins that are linked to cancer pathogenesis. By annotating these reagents, we aim to share our perspectives on an informative 'epigenomic toolbox' of broad utility to the research community.
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Change history
10 March 2017
Supplementary information S1-S6 (tables) for this article have been replaced, with several minor errors in the tables and references corrected.
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Acknowledgements
R.W.J. is funded by project and programme grants from the National Health and Medical Research Council of Australia (NHMRC), an NHMRC Senior Principal Research Fellowship and grants from the Cancer Council Victoria and the Victorian Cancer Agency (VCA). C.J.O. is supported by a Fellow Award from the Leukemia and Lymphoma Society (5667–13) and by a US National Cancer Institute (NCI) Pathway to Independence Award (K99CA190861). J.S. is supported by a Fellowship from the Eva & Les Erdi Snowdome Foundation/VCA and project grants from the Cancer Council of Victoria and NHMRC. J.E.B. is supported by research grants from the US National Institutes of Health (NIH) (R01-CA176745 and P01-CA066996), the William Lawrence & Blanche Hughes Foundation and a Leukemia & Lymphoma Society Specialized Center of Research (SCOR) grant.
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Competing interests
R.W.J. has received research grants and honorarium from Novartis, Astra-Zeneca, AbbVie and Roche. J.S. has received speakers' bureaux/honoraria from Bristol-Myers Squibb (BMS), Celgene and Novartis, travel sponsorships from BMS and Novartis, and research funding from BMS. J.E.B. is a founder of Tensha Therapeutics, a biotechnology company that develops drug-like derivatives of JQ1 as investigational cancer therapies and is a current employee of Novartis.
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DATABASES
FURTHER INFORMATION
Supplementary information
Supplementary information S1 (table)
Histone methylation probes (PDF 3337 kb)
Supplementary information S2 (table)
Histone acetyltransferase inhibitors (PDF 1135 kb)
Supplementary information S3 (table)
Metal-dependent histone deacetylase inhibitors (PDF 2974 kb)
Supplementary information S4 (table)
NAD+-dependent deacetylase (sirtuin) activators and inhibitors (PDF 1610 kb)
Supplementary information S5 (table)
Bromodomain inhibitors (PDF 1436 kb)
Supplementary information S6 (table)
DNA methyltransferase inhibitors (PDF 1820 kb)
Glossary
- Epigenomic
-
A general descriptor that refers to the complete characteristic features of the chromatin interface — transcription factor binding, nucleosome positioning and modifications, and DNA modifications — that can influence transcriptional aspects of gene expression control.
- Gene control
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A term that generally refers to the multiple regulatory aspects of expressing a unique gene product, from initial mechanisms of transcription to the final processing and localization of mature proteins.
- Integrated epigenomics
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The use of epigenome-wide measurements to resolve global and gene locus-specific characteristics of chromatin features.
- Cereblon
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A protein that serves as an adaptor for a cullin-4–RING ubiquitin ligase complex. Thalidomide analogues bind to cereblon, redirecting its ubiquitin ligase activity towards neosubstrates in the cell.
- Euchromatin
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A loosely packed chromatin state that is generally more permissive to transcription.
- Heterochromatin
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A more tightly packed chromatin state generally associated with transcriptional repression.
- Pharmacokinetics
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The study of drug disposition over time once it enters the body, including factors such as absorption, distribution, metabolism and excretion.
- MYST family
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A highly conserved family of histone acetyltransferases (HATs) containing an acetyl–CoA-binding motif and a zinc finger domain. Dysregulation of MYST family HATs has been linked to several cancers.
- NUT midline carcinoma
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(NMC). A rare, aggressive epithelial cancer with a predilection for midline structures. This malignancy is driven by oncogenic fusions of either BRD3 or BRD4 to the entire NUT protein. Constitutive activation and abnormal nuclear localization of NUT permits aberrant association with acetylated chromatin.
- Super-enhancers
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Clusters of enhancers bound by an especially high amount of master regulatory transcription factors found in proximity to genes integral to cell identity.
- Synthetic lethality
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Refers to an effect whereby a single drug (or mutation) does not affect cell viability in isolation but when combined, markedly synergizes to induce cell death.
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Shortt, J., Ott, C., Johnstone, R. et al. A chemical probe toolbox for dissecting the cancer epigenome. Nat Rev Cancer 17, 160–183 (2017). https://doi.org/10.1038/nrc.2016.148
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DOI: https://doi.org/10.1038/nrc.2016.148
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