ABSTRACT
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.
Subject(s)
Cell Transformation, Neoplastic , Drosophila Proteins , Drosophila melanogaster , Epigenesis, Genetic , Neoplasms , Polycomb-Group Proteins , Animals , Female , Male , Cell Transformation, Neoplastic/genetics , Drosophila melanogaster/cytology , Drosophila melanogaster/genetics , Drosophila melanogaster/metabolism , Drosophila Proteins/metabolism , Drosophila Proteins/genetics , Gene Expression Regulation, Neoplastic , Gene Silencing , Janus Kinases/genetics , Janus Kinases/metabolism , Neoplasms/genetics , Neoplasms/pathology , Polycomb-Group Proteins/deficiency , Polycomb-Group Proteins/genetics , Polycomb-Group Proteins/metabolism , Repressor Proteins/genetics , Repressor Proteins/metabolism , Signal Transduction/genetics , STAT Transcription Factors/genetics , STAT Transcription Factors/metabolismABSTRACT
Polycomb repressive complexes 1 and 2 have been historically described as transcriptional repressors, but recent reports suggest that PRC1 might also support activation, although the underlying mechanisms remain elusive. Here, we show that stage-specific PRC1 binding at a subset of active promoters and enhancers during Drosophila development coincides with the formation of three-dimensional (3D) loops, an increase in expression during development and repression in PRC1 mutants. Dissection of the dachshund locus indicates that PRC1-anchored loops are versatile architectural platforms that persist when surrounding genes are transcriptionally active and fine-tune their expression. The analysis of RING1B binding profiles and 3D contacts during neural differentiation in mice suggests that this role is conserved in mammals.
