Transient loss of Polycomb components induces an epigenetic cancer fate

V Parreno; V Loubiere; B Schuettengruber; L Fritsch; C C Rawal; M Erokhin; B Győrffy; D Normanno; M Di Stefano; J Moreaux; N L Butova; I Chiolo; D Chetverina; A-M Martinez; G Cavalli

doi:10.1038/s41586-024-07328-w

Transient loss of Polycomb components induces an epigenetic cancer fate

Nature. 2024 Apr 24. doi: 10.1038/s41586-024-07328-w. Online ahead of print.

Authors

V Parreno^#¹, V Loubiere^#^{1

2}, B Schuettengruber¹, L Fritsch¹, C C Rawal³, M Erokhin⁴, B Győrffy^{5

6}, D Normanno¹, M Di Stefano¹, J Moreaux^{1

7

8}, N L Butova³, I Chiolo³, D Chetverina⁴, A-M Martinez⁹, G Cavalli¹⁰

Affiliations

¹ Institute of Human Genetics, CNRS, University of Montpellier, Montpellier, France.
² Research Institute of Molecular Pathology, Vienna BioCenter, Vienna, Austria.
³ University of Southern California, Los Angeles, CA, USA.
⁴ Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia.
⁵ Semmelweis University Department of Bioinformatics, Budapest, Hungary.
⁶ Department of Biophysics, Medical School, University of Pécs, Pécs, Hungary.
⁷ Department of Biological Hematology, CHU Montpellier, Montpellier, France.
⁸ UFR Medicine, University of Montpellier, Montpellier, France.
⁹ Institute of Human Genetics, CNRS, University of Montpellier, Montpellier, France. anne-marie.martinez@igh.cnrs.fr.
¹⁰ Institute of Human Genetics, CNRS, University of Montpellier, Montpellier, France. giacomo.cavalli@igh.cnrs.fr.

^# Contributed equally.

PMID: 38658752
DOI: 10.1038/s41586-024-07328-w

Abstract

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^3-6, 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.