Transient loss of Polycomb components induces an epigenetic cancer fate

Although cancer initiation and progression are generally associated with the accumulation of somatic mutations, substantial epigenomic alterations underlie many aspects of tumorigenesis and cancer susceptibility, suggesting that genetic mechanisms might not be the only drivers of malignant transformation. However, whether purely non-genetic mechanisms are sufficient to initiate tumorigenesis irrespective of mutations is 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 signaling pathway and zfh1, the fly homolog of the ZEB1 oncogene, whose aberrant activation is required for Polycomb-induced tumorigenesis. These data show that a reversible perturbation of Polycomb Group protein levels can induce cancer in the absence of driver mutations, suggesting that tumors can emerge through epigenetic dysregulation leading to inheritance of altered cell fates. Overall design: Characterization of ph-dependent tumors transcriptomes, chromatin accesibility (ATAC-Seq) and genomic DNA.