Abstract
Cancer is both a genetic and an epigenetic disease. Inactivation of tumour-suppressor genes by epigenetic changes is frequently observed in human cancers, particularly as a result of the modifications of histones and DNA methylation. It is therefore important to understand how these damaging changes might come about. By studying tumorigenesis in the Drosophila eye, here we identify two Polycomb group epigenetic silencers, Pipsqueak and Lola, that participate in this process. When coupled with overexpression of Delta, deregulation of the expression of Pipsqueak and Lola induces the formation of metastatic tumours. This phenotype depends on the histone-modifying enzymes Rpd3 (a histone deacetylase), Su(var)3-9 and E(z), as well as on the chromodomain protein Polycomb. Expression of the gene Retinoblastoma-family protein (Rbf ) is downregulated in these tumours and, indeed, this downregulation is associated with DNA hypermethylation. Together, these results establish a mechanism that links the Notch–Delta pathway, epigenetic silencing pathways and cell-cycle control in the process of tumorigenesis.
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Acknowledgements
We thank J. Müller, E. Giniger, A. Schwendemann, G. Reuter, F. Lyko, W. Chia, and A. Baonza for reagents; the Bloomington Stock Centre and Exelixis for fly stocks; the Developmental Studies Hybridoma Bank for antibodies; E. Ballesta-Illan for technical assistance; F. J. Garcia-Cozar for sharing quantitative RT–PCR expertise; L. A. Garcia-Alonso, J. Galceran and F. Viana for critically reading the manuscript; and M. Sefton for improvements to the manuscript. I.G.G. is a fellow of the CSIC I3P Programme. This work was supported by grants from the ‘Ministerio de Educación y Ciencia’ of Spain and a European Molecular Biology Organization Young Investigator Award to M.D. Author Contributions D.F-M. conceived the experiment to isolate the mutants; D.F-M, I.G-G, D.M.V, FJ.G-A. and J.B. performed the experiments; and M.D. designed the experiments, carried out the data analysis and wrote the paper.
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Supplementary information
Supplementary Table 1
EP and GS lines in the lola and psq region. (DOC 71 kb)
Supplementary Figure 1
Map of the EP and GS lines in the intron of lola gene, RT-PCR and in situ hybridisation analyses of the expression of lola and psq in the eyeful GS line. (PDF 190 kb)
Supplementary Figure 2
Images showing representative individuals of EMS-induced revertants of eyeful. (PDF 173 kb)
Supplementary Figure 3
Mutations in the BTB region of psq and lola associated with reversion of the eyeful phenotype and comparison of BTB domains of Drosophila proteins and human BCL-6 and PLZF. (PDF 405 kb)
Supplementary Figure 4
Psq and Lola behave as epigenetic silencers in vivo. (PDF 185 kb)
Supplementary Notes
This file contains Supplementary Methods and Supplementary Figure Legends. (DOC 161 kb)
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Ferres-Marco, D., Gutierrez-Garcia, I., Vallejo, D. et al. Epigenetic silencers and Notch collaborate to promote malignant tumours by Rb silencing. Nature 439, 430–436 (2006). https://doi.org/10.1038/nature04376
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DOI: https://doi.org/10.1038/nature04376
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