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

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. An indirect route to cancer A common feature in human cancer cells is the inactivation of tumour-suppressor genes via modifications to histones and DNA methylation. To fully understand the cancer-producing process it is important to establish how these ‘epigenetic’ changes occur. A study in the Drosophila eye shows that two nuclear proteins, Pipsqueak and Lola, act as epigenetic silencers when coupled with overexpression of the growth regulator Delta, to produce metastatic tumours. This process requires the presence of histone-modifying enzymes and the chromodomain protein Polycomb. Expression of Retinoblastoma-family protein gene was also downregulated in these tumours. This labyrinthine mechanism therefore unites Notch–Delta signalling, epigenetic silencing and cell-cycle control in one tumour-producing process. This discovery will not only help to clarify aspects of normal and tumour growth, but may also lead to new tests for cancer.