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bioRxiv · 10.1101/2023.01.04.522799

Transient loss of Polycomb components induces an epigenetic cancer fate

Parreno, V.·LOUBIERE, V.·Schuettengruber, B.·Erokhin, M.·Gyorrfy, B.·Di Stefano, M.·Fritsch, L.·Moreaux, J.·Chetverina, D.·Martinez, A.-M.·Cavalli, G.
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Abstract

Cell fate depends on genetic, epigenetic and environmental inputs that are interconnected, making it difficult to disentangle their respective contributions to cell fate decisions1-3, and epigenetic reprogramming is a major contributor to tumor plasticity and adaptation4-6. Although cancer initiation and progression are generally associated with the accumulation of somatic mutations7,8, substantial epigenomic alterations underlie many aspects of tumorigenesis and cancer susceptibility9-18, suggesting that genetic mechanisms alone may not be sufficient to drive malignant transformations19-23. However, whether purely non-genetic reprogramming mechanisms are sufficient to initiate tumorigenesis irrespective of mutations is 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 JNK and JAK-STAT signalling pathways and zfh1, the fly homolog of the ZEB1 oncogene, which we show to be a necessary driver of the cancer fate. These data show that a reversible perturbation of Polycomb-Group protein levels can induce cancer in the absence of driver mutations and suggest that this is achieved through epigenetic inheritance of altered cell fates.

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Parreno, V., LOUBIERE, V., Schuettengruber, B., Erokhin, M., Gyorrfy, B., Di Stefano, M., Fritsch, L., Moreaux, J., Chetverina, D., Martinez, A.-M., Cavalli, G.. 2023-01-04. Transient loss of Polycomb components induces an epigenetic cancer fate. https://doi.org/10.1101/2023.01.04.522799

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