Epigenetic silencers and Notch collaborate to promote malignant tumours by Rb silencing

Nature. 2006 Jan 26;439(7075):430-6. doi: 10.1038/nature04376.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • CpG Islands / genetics
  • DNA Methylation
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / genetics
  • Epigenesis, Genetic / genetics*
  • Gene Silencing*
  • Genes, Retinoblastoma / genetics*
  • Histone Deacetylase 1
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism
  • Histones / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Nuclear Proteins / genetics
  • Phenotype
  • Polycomb Repressive Complex 1
  • Promoter Regions, Genetic / genetics
  • Receptors, Notch / genetics
  • Receptors, Notch / metabolism*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Retinoblastoma / genetics*
  • Retinoblastoma / metabolism
  • Retinoblastoma / pathology*
  • Retinoblastoma Protein / genetics
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription, Genetic / genetics

Substances

  • Drosophila Proteins
  • Histones
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Nuclear Proteins
  • Pc protein, Drosophila
  • Rbf protein, Drosophila
  • Receptors, Notch
  • Repressor Proteins
  • Retinoblastoma Protein
  • Transcription Factors
  • delta protein
  • lola protein, Drosophila
  • psq protein, Drosophila
  • Polycomb Repressive Complex 1
  • HDAC1 protein, Drosophila
  • Histone Deacetylase 1
  • Histone Deacetylases