Department of Molecular and Computational Biology, University of Southern California, 1050 Childs Way, Los Angeles, CA, 90089, USA.
Institute of Human Genetics, CNRS, University of Montpellier, Montpellier, France.
Histochem Cell Biol. 2024 Jul;162(1-2):133-147. doi: 10.1007/s00418-024-02302-z. Epub 2024 Jun 18.
Cancer initiation and progression are typically associated with the accumulation of driver mutations and genomic instability. However, recent studies demonstrated that cancer can also be driven purely by epigenetic alterations, without driver mutations. Specifically, a 24-h transient downregulation of polyhomeotic (ph-KD), a core component of the Polycomb complex PRC1, is sufficient to induce epigenetically initiated cancers (EICs) in Drosophila, which are proficient in DNA repair and characterized by a stable genome. Whether genomic instability eventually occurs when PRC1 downregulation is performed for extended periods of time remains unclear. Here, we show that prolonged depletion of PH, which mimics cancer initiating events, results in broad dysregulation of DNA replication and repair genes, along with the accumulation of DNA breaks, defective repair, and widespread genomic instability in the cancer tissue. A broad misregulation of H2AK118 ubiquitylation and to a lesser extent of H3K27 trimethylation also occurs and might contribute to these phenotypes. Together, this study supports a model where DNA repair and replication defects accumulate during the tumorigenic transformation epigenetically induced by PRC1 loss, resulting in genomic instability and cancer progression.
癌症的发生和发展通常与驱动突变和基因组不稳定性的积累有关。然而，最近的研究表明，癌症也可以纯粹由表观遗传改变驱动，而没有驱动突变。具体来说，在果蝇中，短暂地（24 小时）下调多梳抑制复合物 1（PRC1）的核心组成部分 Polyhomeotic（ph-KD），足以诱导表观遗传起始的癌症（EIC），这些细胞擅长 DNA 修复，其基因组稳定。当 PRC1 下调持续较长时间时，是否会最终发生基因组不稳定性尚不清楚。在这里，我们表明，PH 的长期耗竭（模拟癌症起始事件）会导致 DNA 复制和修复基因的广泛失调，以及 DNA 断裂、修复缺陷和广泛的基因组不稳定性在癌症组织中的积累。H2AK118 泛素化的广泛失调以及 H3K27 三甲基化的程度较轻也会发生，这可能有助于这些表型。总之，这项研究支持了这样一种模型，即 PRC1 缺失诱导的表观遗传肿瘤发生过程中，DNA 修复和复制缺陷逐渐积累，导致基因组不稳定和癌症进展。
