Key Points
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Transcriptional programmes established during embryogenesis are transmitted to daughter cells of the adult so that each cell maintains its appropriate identity, a process referred to as cellular or transcriptional memory. Loss of cellular memory can lead to the spurious transcription of oncogenes and silencing of tumour suppressors, which predisposes to cancer.
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Polycomb group (PcG) and trithorax group (TrxG) proteins affect covalent modifications of histone tails, the position or composition of nucleosomes, as well as DNA methylation, thereby affecting chromatin structure and so transcriptional status. In general, PcG proteins repress — whereas TrxG proteins activate — gene expression.
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Gain of PcG and loss of TrxG function occurs in various human cancers, which is consistent with the idea that tumour cells have stem-like characteristics. This concept is supported by the observation that tumour cells have gene expression profiles that are similar to that of embryonic cells.
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The balance between PcG and TrxG proteins affects the expression of genes that induce cellular senescence — a tumour suppressive mechanism that opposes cellular proliferation.
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PcG–TrxG-mediated chromatin dynamics affects the expression of genes that regulate apoptosis, a process that controls unscheduled cellular proliferation by inducing cell death. PcG proteins can recruit proteins that transcriptionally silence genes encoding components of the apoptotic machinery.
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PcG–TrxG complexes function to maintain the integrity of the genome. The observation that loss of TrxG chromatin remodelling proteins predispose to cancer, even in the absence of genomic lesions, implies that modulation of PcG–TrxG function can be used to treat cancer.
Abstract
The discovery that cancer can be governed above and beyond the level of our DNA presents a new era for designing therapies that reverse the epigenetic state of a tumour cell. Understanding how altered chromatin dynamics leads to malignancy is essential for controlling tumour cells while sparing normal cells. Polycomb and trithorax group proteins are evolutionarily conserved and maintain chromatin in the 'off' or 'on' states, thereby preventing or promoting gene expression, respectively. Recent work highlights the dynamic interplay between these opposing classes of proteins, providing new avenues for understanding how these epigenetic regulators function in tumorigenesis.
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Acknowledgements
The author would like to thank to J. Duffy and Y.-N. Chang for assistance in preparing this manuscript, and to members of her laboratory for helpful discussions.
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Glossary
- Cancer stem cell hypothesis
-
The theory that tumours are composed of a heterogeneous population of cells, including a subset of relatively rare cancer stem cells or 'tumour-propagating' cells that are essential for malignancy.
- Clonal evolution model
-
The theory that tumour-propagating cells make up a considerable proportion of cells in a tumour, and that the malignant state is the consequence of the selection of dominant clones in the population.
- Body segment
-
Transcriptional cascades set up during the development of D. melanogaster partition the embryo into 14 sections or 'parasegments' that correspond to the final anatomical regions of the adult.
- Histone code
-
The concept that the establishment and interpretation of an intricate pattern of histone tail modifications orchestrate chromatin dynamics and gene expression.
- SET domain
-
An approximately 130 amino acid-long motif that provides the HMT activity in various proteins that methylate specific lysine residues of histones as well as other protein substrates.
- Polycomb repressive element
-
PRE. Specific DNA sequence identified in D. melanogaster that is recognized and bound by PRC2 complexes.
- Chromodomain
-
An approximately 60 amino acid-long motif originally discovered in HP1 and PcG proteins from D. melanogaster; it is present in various chromatin regulating proteins.
- RING finger domain
-
An ∼40–60 residue Cys4-His-Cys3-containing motif that binds zinc, and facilitates interactions with DNA, RNA, proteins and lipids.
- SWI2–SNF2
-
A complex identified in yeast that is required for transcriptional activation of ∼7% of the genome, including the mating type switch (SWI) and the sucrose non-fermenting (SNF) genes for which SWI2–SNF2 are named.
- Bromodomain
-
A motif that binds acetylated lysines present on histone tails.
- PHD finger
-
Around 50–80 residues containing the Cys4-His-Cys3 motif originally identified in Arabidopsis thaliana that binds specifically modified histones.
- Chromosome engineering
-
A Cre-loxP-based embryonic stem cell technology that enables the generation of mouse models harbouring defined chromosome rearrangements such as deletions, duplications, inversions and translocations.
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Mills, A. Throwing the cancer switch: reciprocal roles of polycomb and trithorax proteins. Nat Rev Cancer 10, 669–682 (2010). https://doi.org/10.1038/nrc2931
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DOI: https://doi.org/10.1038/nrc2931
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