Abstract
Although cancer initiation and progression are generally associated with the accumulation of somatic mutations 1,2 , substantial epigenomic alterations underlie many aspects of tumorigenesis and cancer susceptibility 3–6 , suggesting that genetic mechanisms might not be the only drivers of malignant transformation 7 . However, whether purely non-genetic mechanisms are sufficient to initiate tumorigenesis irrespective of mutations has been unknown. Here, we show that a transient perturbation of transcriptional silencing mediated by Polycomb group proteins is sufficient to induce an irreversible switch to a cancer cell fate in Drosophila . This is linked to the irreversible derepression of genes that can drive tumorigenesis, including members of the JAK–STAT signalling pathway and zfh1 , the fly homologue of the ZEB1 oncogene, whose aberrant activation is required for Polycomb perturbation-induced tumorigenesis. These data show that a reversible depletion of Polycomb proteins can induce cancer in the absence of driver mutations, suggesting that tumours can emerge through epigenetic dysregulation leading to inheritance of altered cell fates.