Key Points
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Enhancer malfunction is a key process that drives the aberrant regulation of oncogenes in cancer.
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Enhancer variants contribute more than any other known mechanism to heritable cancer predisposition.
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Somatic mutations affecting enhancers are common in sporadic tumours. They include copy number alterations that increase the strength of an enhancer, structural rearrangements that direct enhancers to new targets and point mutations or small insertions or deletions (indels) that create new enhancers by altering transcription factor binding sites.
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Epigenetic mechanisms also commonly alter enhancer activities in cancer.
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During normal development and homeostasis, very strong enhancers or super-enhancers are found near lineage-specifying genes. During tumorigenesis, super-enhancers commonly form de novo near oncogenes.
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Strong enhancer activities in cancer cells lock the growth regulatory network to an 'on' state, driving uncontrolled proliferation.
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Enhancer malfunction can be targeted for cancer therapy. Although transcription is a general property of all cells, cancer cells are more dependent on increased transcription levels from enhancers and, thus, are more sensitive to enhancer inhibition than their normal counterparts.
Abstract
Enhancer elements function as the logic gates of the genetic regulatory circuitry. One of their most important functions is the integration of extracellular signals with intracellular cell fate information to generate cell type-specific transcriptional responses. Mutations occurring in cancer often misregulate enhancers that normally control the signal-dependent expression of growth-related genes. This misregulation can result from trans-acting mechanisms, such as activation of the transcription factors or epigenetic regulators that control enhancer activity, or can be caused in cis by direct mutations that alter the activity of the enhancer or its target gene specificity. These processes can generate tumour type-specific super-enhancers and establish a 'locked' gene regulatory state that drives the uncontrolled proliferation of cancer cells. Here, we review the role of enhancers in cancer, and their potential as therapeutic targets.
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Acknowledgements
The authors wish to thank M. Taipale and E. Kaasinen for careful reading of the manuscript and helpful comments.
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Glossary
- Variant histones
-
Non-allelic variant forms of the canonical histone proteins, such as H2AX and H3.3, that can be incorporated into nucleosomes in a replication-independent manner and serve to regulate multiple processes, including transcription and DNA repair.
- Expression quantitative trait loci
-
(eQTLs). Regions of the genome that account for quantitative variability in the expression of a given gene. These can either be linked (in cis) or unlinked (in trans) to the target gene. They are mapped by measuring the expression levels of genes and correlating them with the individual genotypes.
- DNase I hypersensitive sites
-
Active regions of the genome that are depleted of nucleosomes. The open chromatin conformation of these regions makes them hypersensitive to digestion by the enzyme DNase I.
- Effect sizes
-
Quantitative measures of the magnitude of a given effect. For example, in genome-wide association studies (GWAS), the effect size is given as an odds ratio, describing the relative increase in cancer risk of individuals carrying the risk variant.
- Odds ratio
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The association between the presence or absence of a variant (for example, a particular allele of a single nucleotide polymorphism) and the presence or absence of a trait (for example, cancer) in the population. The odds of occurrence of the variant is determined in groups of subjects with and without the trait; the odds ratio is the ratio of the odds of occurrence of the variant in people with the trait to the odds of occurrence of the variant in people without the trait.
- tag SNPs
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Genotyped single nucleotide polymorphisms (SNPs) that are used to predict the genotypes of other nearby SNPs. The SNP that contributes to cancer predisposition can either be the tag SNP itself, or more commonly, another SNP that is in linkage disequilibrium with the tag SNP.
- Insulated chromosome neighbourhoods
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Large DNA loops containing genes and enhancers, in which the expression of the genes is controlled by the enhancers within the loop, but is insulated from influence by enhancers residing outside the loop. It is thought that these loops are formed by an interaction between two CCCTC-binding factor (CTCF) and cohesin proteins bound at the loop boundaries.
- Microsatellite instability
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Microsatellite DNA corresponds to short stretches of highly repetitive 1–5 bp sequences. Some cancer cells display high mutation rates at such microsatellite DNA repeats. This microsatellite instability is a consequence of mutational or epigenetic inactivation of genes involved in DNA mismatch repair.
- Cyclin-dependent kinase 7
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(CDK7). Part of the multi-protein transcription factor IIH complex that is required for general transcription. Within this complex, CDK7 phosphorylates the carboxy-terminal domain of RNA polymerase II.
- BET-bromodomain protein
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Member of a protein family that contains conserved bromodomains that recognize acetyl-lysine on proteins, including histones. Within this group, bromodomain protein 2 (BRD2), BRD3, BRD4 and BRDT constitute a family of bromodomain and extra-terminal (BET) proteins that regulate transcription.
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Sur, I., Taipale, J. The role of enhancers in cancer. Nat Rev Cancer 16, 483–493 (2016). https://doi.org/10.1038/nrc.2016.62
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DOI: https://doi.org/10.1038/nrc.2016.62
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