Polycomb repressive complexes in development and disease

In addition to the developmental defects of PcG mutants in Drosophila, genetic studies in mice have shown that many PcG proteins are essential for normal development, with knockout phenotypes ranging from early embryonic lethality to homeotic transformation or perinatal lethality. Furthermore, mutations in genes encoding PcG proteins are associated with several human congenital disorders, underlining their key role during normal development^1,2.

Also, PRC function is often disrupted in many different types of human cancer through deregulation of expression levels or somatic mutations of genes encoding PcG proteins or histone mutants leading to a substitution of the PRC2 substrate lysine (H3K27M)^3,4.

Therapeutic targeting of PcG proteins

The high frequency of cancer-associated mutations along with the promise of ‘epigenetic therapies’ has led to the development of various chemical compounds targeting PcG proteins. These include small-molecule inhibitors blocking the catalytic activity of EZH2 or preventing H3K27me3-binding by EED or CBX proteins or disrupting other protein-protein interfaces. Excitingly, the first EZH2 inhibitor, Tazemetostat, was recently FDA-approved for the treatment of follicular lymphoma and epithelioid sarcoma. Several other compounds are under preclinical and clinical development, including those targeting the catalytic activity of EZH2 or the integrity of PRC2 through degradation or obstruction of binding surfaces⁵.

You can find more details on the role of PcG proteins in disease in our full guide.

References

1. Deevy, O., Bracken, A. P. PRC2 functions in development and congenital disorders Development 146 , (2019)
2. Piunti, A., Shilatifard, A. Epigenetic balance of gene expression by Polycomb and COMPASS families Science 352 , (2016)
3. Schuettengruber, B., Bourbon, H. M., Di Croce, L., et al. Genome regulation by polycomb and trithorax: 70 years and counting Cell 171 ,34-57 (2017)
4. Bracken, A. P., Brien, G. L., Verrijzer, C. P. Dangerous liaisons: interplay between SWI/SNF, NuRD, and Polycomb in chromatin regulation and cancer Genes Dev 33 ,936-959 (2019)
5. Dockerill, M., Gregson, C., DH, O. D. Targeting PRC2 for the treatment of cancer: an updated patent review (2016-2020) Expert Opin Ther Pat , (2020)