Mutations in, and the altered expression of, epigenetic modifiers are pervasive in human tumours, making epigenetic factors attractive antitumour targets. The open-versus-closed chromatin state within the cells-of-origin of cancer correlates with the uneven distribution of mutations. However, the long-term effect of targeting epigenetic modifiers on mutability in patients with cancer is unclear. Here, we increased chromatin accessibility by deleting the histone H3 lysine 9 (H3K9) methyltransferase G9a in murine epidermis and show that this does not alter the single nucleotide variant burden or global genomic distribution in chemical mutagen-induced squamous tumours. G9a-depleted tumours develop after a prolonged latency compared with their wild-type counterparts, but are more aggressive and have an expanded cancer progenitor pool, pronounced genomic instability and frequent loss-of-function p53 mutations. Thus, we call for caution when assessing long-term therapeutic benefits of chromatin modifier inhibitors, which may promote more aggressive disease.

中文翻译：

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G9a的丢失会保留突变模式，但会增加染色质的可及性，基因组不稳定性和皮肤肿瘤的侵袭性。

表观遗传修饰因子的突变和表达的改变在人类肿瘤中普遍存在，使表观遗传因子成为抗肿瘤靶标。癌症起源细胞内染色质的开放与封闭状态与突变的不均匀分布有关。然而，尚不清楚靶向表观遗传修饰剂对癌症患者变异性的长期影响。在这里，我们通过删除小鼠表皮中的组蛋白H3赖氨酸9（H3K9）甲基转移酶G9a增加了染色质的可及性，并表明这不会改变化学诱变诱导的鳞状上皮细胞的单核苷酸变异体负担或整体基因组分布。与野生型对应物相比，耗竭了G9a的肿瘤在潜伏期延长后会发展，但更具侵略性，并且拥有广泛的癌症祖细胞，明显的基因组不稳定和频繁丧失功能的p53突变。因此，在评估染色质修饰剂抑制剂的长期治疗效果时，我们需要谨慎，这可能会促进更具侵略性的疾病。