近日，法国蒙彼利埃大学G. Cavalli等研究人员合作发现，多梳组分的瞬时丧失会诱导出一种表观遗传的癌症命运。相关论文于2024年4月24日在线发表在《自然》杂志上。

研究人员发现，由多梳家族蛋白介导的转录沉默的短暂扰动足以诱导果蝇不可逆地转入癌细胞命运。这与可驱动肿瘤发生的基因的不可逆抑制有关，这些基因包括JAK-STAT信号通路的成员和ZEB1致癌基因的果蝇同源物zfh1。这些数据表明，在没有驱动基因突变的情况下，多梳蛋白的可逆损耗可诱发癌症，这表明肿瘤可通过表观遗传失调导致细胞命运改变而出现。

据悉，虽然癌症的发生和发展通常与体细胞突变的积累有关，但肿瘤发生和癌症易感性的许多方面都与大量表观基因组改变有关，这表明遗传机制可能不是恶性转化的唯一驱动因素。然而，无论基因突变与否，纯粹的非遗传机制是否足以启动肿瘤发生一直是个未知数。

附：英文原文

Title: Transient loss of Polycomb components induces an epigenetic cancer fate

Author: Parreno, V., Loubiere, V., Schuettengruber, B., Fritsch, L., Rawal, C. C., Erokhin, M., Gyrffy, B., Normanno, D., Di Stefano, M., Moreaux, J., Butova, N. L., Chiolo, I., Chetverina, D., Martinez, A.-M., Cavalli, G.

Issue&Volume: 2024-04-24

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. A transient perturbation of transcriptional silencing mediated by Polycomb proteins is sufficient to induce an epigenetic cancer cell fate in Drosophila in the absence of driver mutations.

DOI: 10.1038/s41586-024-07328-w

Source: https://www.nature.com/articles/s41586-024-07328-w