Emerging roles for Polycomb proteins in cancer

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The activities of the heterogeneous Polycomb (PcG) group of proteins ensure that the developmental processes of proliferation and cellular identity establishment are carried out correctly. PcG proteins assemble stable multiprotein complexes that, together with additional factors, maintain their target genes in a transcriptionally repressive state. The biochemical and functional features of PcG proteins have been extensively investigated over the years. Here we analyse the biochemical and mechanistic proprieties of PcG proteins with respect to recent advances that link the genetic alterations of PcG activity to cancer development.

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Biochemical and functional heterogeneity of Polycomb repressive complexes

Polycomb (PcG) proteins form two distinct multiprotein repressive complexes, PRC1 and PRC2. While PRC1 is required to deposit histone H2AK119 ubiquitination (H2Aub) through the activity of the E3 Ligases Ring1a or Ring1b [1], PRC2 catalyses histone H3 lysine 27 tri-methylation (H3K27me3), with the methyltransferases EZH1 or EZH2 [2, 3]. Both class of enzymes requires stable association with structural proteins to be active: Ring1a or Ring1b require dimerization with one of the six PCGF subunits

PRC recruitment and hierarchies

The mechanisms by which PRC1 and PRC2 complexes are recruited to chromatin and then maintained in a bound state are not fully clear (see also other recent [12, 23, 24, 25, 26, 27, 28, 29, 30]). This process requires a transient interaction with DNA-binding transcription factors, the presence of PRC subunits that can bind both DNA and specific histone modifications, association with non-coding RNAs (ncRNA), and the absence of active RNA Polymerase II (RNA Pol II) (Figure 2). Here, it is

Mechanisms of developmental control

While proliferation is mainly promoted by PRC1 and PRC2 through their direct repression of the Cdkn2a locus (Ink4a-Arf) and their indirect support of DNA replication [44, 45, 46, 47, 48, 49], cellular identity is established by cell type–specific repression of non-lineage–specific transcription [50, 51, 52]. In other words, PcG proteins ensure that the non-required developmental transcription programme remains silenced during lineage specification to achieve and maintain correct cellular

Pathological outcome of deregulated PRC activity

As the basis of cancer development is the loss of cellular identity, it is not surprising that epigenetic enzymes turned out to be one of the most frequently mutated genes family in human cancer [65], with PcGs playing a central role [66, 67]. The discovery of the first mammalian PcG protein Bmi1 came from a genetic screen aimed at identifying oncogenes that cooperate with Myc-induced lymphomas in mice [68]. The remaining PcG proteins were classified as oncogenes for many years due to their

Conclusions

It is clear that altering the homeostasis of PcG activity can adversely affect cellular identity, thereby promoting cancer development in a tissue-specific and/or cell type–specific fashion. This process seems to involve both the catalytic and non-catalytic functions of PcG proteins, primarily affecting PRC2 rather than PRC1 activity. It is tempting to speculate that PRC1 might have more general, essential functions than PRC2, as suggested by the early embryogenesis defects observed in the

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Author contributions

D.P. and L.D.C. wrote the manuscript.

Acknowledgements

We thank all members of the Pasini and Di Croce laboratories for helpful discussions. We thank Veronica A. Raker for author's editing. The work in the Di Croce laboratory is supported by grants from the Spanish “Ministerio de Educación y Ciencia” (SAF2013-48926-P), AGAUR, La Marato TV3, the Fundación Vencer El Cáncer (VEC), Spanish Ministry of Economy and Competitiveness, “Centro de Excelencia Severo Ochoa 2013-2017” (SEV-2012-0208), and the EU FP7 4DCellFate (277899). The work in the Pasini

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