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  • Review Article
  • Published:

Polycomb group proteins: navigators of lineage pathways led astray in cancer

Nature Reviews Cancer volume 9, pages 773–784 (2009)Cite this article

Key Points

  • The Polycomb group (PcG) proteins regulate cell fate decisions during development and differentiation. They form multiprotein repressive complexes called Polycomb repressive complexes (PRCs), which modify chromatin.

  • The PcG proteins bind and repress the promoters of hundreds of genes encoding proteins with roles in cell fate determination.

  • It is unclear how PcG proteins are displaced and recruited to different subsets of target genes during cell fate decisions. However, cell fate transcription factors (CFTFs) and long non-coding RNAs (ncRNAs) are emerging as potential regulators.

  • There is growing evidence that many PcG target genes are silenced in advanced cancer and that this may be the result of an epigenetic switch to DNA methylation during neoplastic progression.

  • Several PcG proteins are known to be deregulated in cancer. We propose that the deregulation of CFTFs and long ncRNAs also leads to the misexpression of PcG target genes.

Abstract

The Polycomb group (PcG) proteins are transcriptional repressors that regulate lineage choices during development and differentiation. Recent studies have advanced our understanding of how the PcG proteins regulate cell fate decisions and how their deregulation potentially contributes to cancer. In this Review we discuss the emerging roles of long non-coding RNAs (ncRNAs) and a subset of transcription factors, which we call cell fate transcription factors, in the regulation of PcG association with target genes. We also speculate about how their deregulation contributes to tumorigenesis.

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Figure 1: Coordinated action of Polycomb repressive complexes.
Figure 2: Dynamic recruitment and displacement of Polycomb group proteins during lineage specification.
Figure 3: Potential mechanisms by which cell fate transcription factors and long non-coding RNAs function to regulate Polycomb group protein association with target genes during lineage choices and specification.
Figure 4: Gain and loss of cell fate transcription factors may lead to the formation of tumour-initiating cells.

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Acknowledgements

We thank G. Brien for help with Table 1, E. Bernstein for critical reading of the manuscript and members of the Bracken and Helin laboratories for very helpful discussions. Work in the Bracken laboratory is supported by the Smurfit Institute of Genetics, the Adelaide & Meath Hospital, including the National Children's Hospital, and the Trinity College Dublin start-up fund for new lecturers. Work in the Helin laboratory is supported by the Danish National Research Foundation, the Danish Cancer Society, the Novo Nordisk Foundation, the Danish Medical Research Council, the Danish Natural Science Research Council, the Lundbeck Foundation, the Association for International Cancer Research and the Excellence Programme of the University of Copenhagen.

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  1. The Smurfit Institute of Genetics, Trinity College Dublin and The Adelaide & Meath Hospital, including the National Children's Hospital, Dublin, Ireland

    Adrian P. Bracken

  2. Biotech Research and Innovation Centre (BRIC) and Centre for Epigenetics, University of Copenhagen, 22009, Copenhagen, Denmark

    Kristian Helin

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Glossary

Epigenetic

Relating to effects on patterns of gene expression that are heritable through cell division and caused by mechanisms other than changes to the underlying DNA sequence.

Polycomb group proteins

A group of proteins first described in D. melanogaster that are required for normal development. They work in multiprotein complexes, called Polycomb repressive complexes, that establish regions of chromatin in which gene expression is repressed.

Homeobox (Hox) genes

Genes encoding a group of transcription factors that specify the anterior–posterior axis and segment identity of metazoan organisms during early embryonic development.

CDKN2B and CDKN2A loci

A stretch of 45 kb of chromosome 9 (in humans), which is frequently the target of mutation, deletion and epigenetic silencing in cancer. They encode three tumour suppressor proteins: INK4A and INK4B, which function in the RB pathway, and ARF, which functions in the p53 pathway.

Tumour suppressor

The loss of function of a tumour suppressor (by mutation, deletion or epigenetic silencing) contributes to cancer progression.

EZH2

A PcG protein and a histone methyltransferase that, together with EED and SUZ12 in the PRC2 complex, catalyses the trimethylation of histone H3 at lysine K27 (H3K27me3).

DNA methyltransferase

An enzyme that catalyses the transfer of a methyl group to DNA.

BMI1

BMI1 was initially identified as a common site of viral integration in Moloney virus-induced B cell lymphomas. Subsequently, BMI1 was shown to be a member of the PcG family.

Oncogene

A gene that contributes to cancer progression as a consequence of overexpression or of dominantly acting mutations that alter the activity and/or specificity of the gene product.

MicroRNA

These single-stranded RNAs are ∼21 to 23 nucleotides in length and regulate gene expression by partial complementary base pairing to mRNAs and recruitment to the RNA-induced silencing complex to inhibit translation (and possibly increase degradation) of mRNA.

Polycomb repressive element

A DNA sequence of varying length, but often of several hundred base pairs, to which the PcG proteins can be recruited. PREs have been defined in D. melanogaster, but not in other organisms so far. They are composed of a collection of transcription factor binding sites, defined as an 'element'.

CFTF

Any transcription factor that functions to regulate cell fate decisions during differentiation and development.

Embryonic stem cell

A cell derived from the inner cell mass of an early-stage embryo known as a blastocyst in mice and an epiblast in humans. They are immortal, can be propagated in vitro and are pluripotent.

SET domain

A conserved domain that catalyses histone lysine methyltransferase activity and is found in a wide variety of chromatin-modifying proteins, for example EZH2, SU(VAR)H1, MLL1 and G9A.

Chromodomain

A conserved region of around 60 amino acids, found in many of chromatin-interacting proteins, for example HPC1, HP1 and CHD1–9. It is involved in binding to specific methylated lysine residues, as found in histone proteins.

Pluripotent cell

A type of stem cell that is capable of differentiating into all of the derivatives of the three germ layers: ectoderm, endoderm and mesoderm.

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Bracken, A., Helin, K. Polycomb group proteins: navigators of lineage pathways led astray in cancer. Nat Rev Cancer 9, 773–784 (2009). https://doi.org/10.1038/nrc2736

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