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
Reversible histone acetylation plays an important role for chromatin structure and gene expression. The acetylation state of core histones is controlled by histone acetyltransferases and histone deacetylases. Here we report the cloning and characterization of the mouse histone deacetylase 1 (HDAC1) gene. The mouse genome contains several HDAC1-related structures representing the HDAC1 gene and at least three pseudogenes. The HDAC1 gene comprises 14 exons ranging from 49 to 539 bp. Interestingly the murine HDAC1 gene strongly resembles the previously published mouse HDAC2 gene (Zeng et al., J. Biol. Chem. 273 (1998) 28921-28930). The sizes of ten of the 14 exons are identical for both genes and the splicing sites for 11 introns align in identical positions suggesting a gene duplication event. The HDAC1 gene is located only 128 bp downstream from the MARCKS-related protein (MRP) gene in a tail-to-tail orientation. The murine MRP gene was previously mapped to a conserved gene cluster on chromosome 4 sharing linkage homology to human chromosome 1p32-36. The genes for HDAC1 and MRP are co-expressed in a variety of cell types. In the genome of 129SV mice the largest intervening sequence of the HDAC1 gene, intron 3, harbors a complete copy of the endogenous retrovirus MuERV-L. In contrast the HDAC1 gene in other mouse strains such as C57B16, C3H/An and C-RY lacks the retrovirus. Our study provides useful tools for future targeted gene disruption studies.
