1. Instituto de Neurociencias CSIC–UMH, Campus de San Juan, Apartado 18, 03550 Sant Joan, Alicante, Spain
2. Departamento de Bioquimica y Biologia Molecular, Facultad de Ciencias, Universidad de Cadiz, Poligono Rio San Pedro s/n, 11510 Puerto Real, Spain
3. *These authors contributed equally to this work

Correspondence to: Maria Dominguez¹ Correspondence and requests for materials should be addressed to M.D. (Email: m.dominguez@umh.es).

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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