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^3,4,5,6, 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.

虽然癌症的发生和进展通常与体细胞突变的积累相关^1,2，但肿瘤发生和癌症易感性的许多方面都存在显着的表观基因组改变^3,4,5,6，这表明遗传机制可能不是恶性转化的唯一驱动因素。⁷ .然而，无论突变如何，纯粹的非遗传机制是否足以引发肿瘤发生尚不清楚。在这里，我们表明，由 Polycomb 组蛋白介导的转录沉默的短暂扰动足以诱导果蝇中癌细胞命运的不可逆转变。这与驱动肿瘤发生的基因的不可逆去抑制有关，包括 JAK-STAT 信号通路的成员和zfh1 （ ZEB1癌基因的果蝇同源物），其异常激活是 Polycomb 扰动诱导的肿瘤发生所必需的。这些数据表明，在没有驱动突变的情况下，Polycomb 蛋白的可逆性消耗可以诱发癌症，这表明肿瘤可以通过表观遗传失调而出现，从而导致细胞命运改变的遗传。