Transient loss of Polycomb components induces an epigenetic cancer fate

• 成果类型: Article
• 署名作者: Parreno, V.; Loubiere, V.; Schuettengruber, B.; Fritsch, L.; Rawal, C. C.; Erokhin, M.; Gyorffy, B.; Normanno, D.; Di Stefano, M.; Moreaux, J.; Butova, N. L.; Chiolo, I.; Chetverina, D.; Martinez, A-M; Cavalli, G.
• 署名单位: Universite de Montpellier; Centre National de la Recherche Scientifique (CNRS); Vienna Biocenter (VBC); Research Institute of Molecular Pathology (IMP); University of Southern California; Russian Academy of Sciences; Institute of Gene Biology (IGB) of Russian Academy of Sciences; Semmelweis University; University of Pecs; Universite de Montpellier; CHU de Montpellier; Universite de Montpellier
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4176
• DOI: 10.1038/s41586-024-07328-w
• 发表日期: 2024-05-16
• 页码: 688-696
• 关键词: tumor-suppressor activity; cell self-renewal; gene-expression; drosophila; Heterogeneity; PATHWAY; thalidomide; mutations; proteins; GROWTH

摘要

Although cancer initiation and progression are generally associated with the accumulation of somatic mutations(1,2), substantial epigenomic alterations underlie many aspects of tumorigenesis and cancer susceptibility(36) , suggesting that genetic mechanisms might not be the only drivers of malignant transformation(7). However, whether purely non-genetic mechanisms are sufcient 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 sufcient 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 JAKSTAT signalling pathway and zf1, he fy homologue of the ZEB1 oncogene, whose aberrant activation is required for Polycomb perturbationinduced 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.