Activation of conserved developmental signalling pathways, such as Notch, has been observed in human cancers, yet activation of such pathways in animal models seems to be insufficient for tumorigenesis. Dolors Ferres-Marco et al. now report that in a Drosophila melanogaster model the Notch pathway collaborates with epigenetic silencing pathways and cell-cycle control in tumour development.

figure 1

Figure 1

The developing eye in Drosophila is a good model for identifying tumour-inducing mechanisms because it is simple and genetically well-defined. The growth of the eye depends on Notch activation by its ligands Delta and Serrate. The 'large eye' phenotype model, produced by overexpression of Delta, was screened by upregulating genes at random and looking for induced tumour growth (see figure). Ferres-Marco and colleagues found that overexpression of two neighbouring genes, longitudinals lacking ( lola ) and pipsqueak ( psq ) caused tumour formation (see figure). Both Psq and Lola behave as epigenetic silencers of the Polycomb group, which maintain transcriptional repression patterns.

So, do psq and lola contribute to the tumour phenotype when co-activated with the Notch pathway? The authors introduced point mutations into these genes to disrupt their expression — all psq− mutations prevented tumorigenesis and all lola− mutations reduced eye tumour size. Most of the mutations were in the BTB domain of Psq, and, as BTB protein family members are transcriptional repressors and include oncogenes that recruit Polycomb proteins, the authors speculated that deregulated psq and lola could lead to tumorigenesis by epigenetic silencing. As methylation of histone H3 is a central modification in epigenetic control, the authors immunolabelled eye discs with antibodies against histone H3 methylation. A loss or reduction of H3 lysine 4 methylation was observed in the tumour eye discs, and overexpression of Delta significantly reduced H3 methylation too.

The next step was to look at which genes were aberrantly silenced. Such genes are likely to include those involved in the control of the cell cycle, so the authors looked at the transcription of 12 tumour-related genes in the mutant and wild-type eye discs. Transcription of Rbf , a fly homologue of the human retinoblastoma tumour-suppressor gene (RB), was strongly down-regulated in the tumours. Halving Rbf gene dosage enhanced tumour growth, and re-establishing Rbf expression in the eye prevented tumour formation.

These results establish a mechanism that links the Notch–Delta pathway, epigenetic silencing pathways and cell-cycle control in the process of tumorigenesis.