RESUMO
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.
Assuntos
Transformação Celular Neoplásica , Proteínas de Drosophila , Drosophila melanogaster , Epigênese Genética , Neoplasias , Proteínas do Grupo Polycomb , Animais , Feminino , Masculino , Transformação Celular Neoplásica/genética , Drosophila melanogaster/citologia , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Janus Quinases/genética , Janus Quinases/metabolismo , Neoplasias/genética , Neoplasias/patologia , Proteínas do Grupo Polycomb/deficiência , Proteínas do Grupo Polycomb/genética , Proteínas do Grupo Polycomb/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Transdução de Sinais/genética , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/metabolismoRESUMO
Single-molecule techniques have propelled an impressive number of biophysical studies during the last decade. From relatively simple video-microscopy techniques, to sophisticated manipulation and detection apparata, single-molecule techniques are capable of tracking the movements and the reaction trajectories of single enzymatic units. By observing microspheres attached to biomolecules it is possible to follow the motion of molecular motors, or to detect conformational "switching" induced by regulatory proteins. Micromanipulation tools like optical tweezers have been widely applied to understand the mechanisms of linear molecular motors, and have allowed the measurement of the elementary steps and the forces produced by several motor proteins, including myosin, kinesin, and dynein. New experimental assays based on magnetic or optical "wrenches," which are able to apply and detect torques on rotary motors and biopolymers, are opening new possibilities in this field. Here, established and emerging magneto-optical manipulation and video-tracking techniques are reviewed, in the perspective of single molecular motors and regulatory proteins studies.