Although cancer initiation and progression are generally associated with the accumulation
of somatic mutations1,2, substantial epigenomic alterations underlie many aspects
of tumorigenesis and cancer susceptibility3-6, suggesting that genetic mechanisms
might not be the only drivers of malignant transformation7. 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.
