Liver cancer initiation is controlled by AP-1 through SIRT6-dependent inhibition of survivin
Liver cancer initiation is controlled by AP-1 through SIRT6-dependent inhibition of survivin
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DOI：
10.1038/ncb2590
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发表时间：
2012-11-01
影响因子：
21.3
通讯作者：
Wagner, Erwin F.
中科院分区：
文献类型：
--
作者：
Min, Lihua;Ji, Yuan;Wagner, Erwin F.
了解阶段依赖性致癌机制不仅对于开发靶向治疗、而且对于开发诊断标记物和预防策略至关重要。癌症发生过程中的作用机制仍然难以捉摸，这主要是由于缺乏合适的动物模型和人类癌前病变的可用性有限。在这里，我们使用肝癌起始特异性的遗传小鼠模型证明，起始癌细胞的存活是由 c-Jun 控制的，独立于 p53，通过抑制 c-Fos 介导的细胞凋亡。从机制上讲，c-Fos 诱导 SIRT6 转录，后者通过减少组蛋白 H3K9 乙酰化和 NF-κ B 激活来抑制生存素。重要的是，在起始阶段提高 SIRT6 的水平或针对生存素的抗凋亡活性可显着损害癌症的发展。此外，在人类发育不良的肝结节中，但在恶性肿瘤中，没有发现一种特殊的表达模式，即 c-Jun-survivin 增加和 c-Fos-SIRT6 水平减弱。这些结果揭示了肝脏肿瘤发生过程中连接应激反应和组蛋白修饰的调控网络，可以有针对性地预防肝脏肿瘤发生。
Understanding stage-dependent oncogenic mechanisms is critical to develop not only targeted therapies, but also diagnostic markers and preventive strategies. The mechanisms acting during cancer initiation remain elusive, largely owing to a lack of suitable animal models and limited availability of human precancerous lesions. Here we show using genetic mouse models specific for liver cancer initiation, that survival of initiated cancer cells is controlled by c-Jun, independently of p53, through suppressing c-Fos-mediated apoptosis. Mechanistically, c-Fos induces SIRT6 transcription, which represses survivin by reducing histone H3K9 acetylation and NF-kappa B activation. Importantly, increasing the level of SIRT6 or targeting the anti-apoptotic activity of survivin at the initiation stage markedly impairs cancer development. Moreover, in human dysplastic liver nodules, but not in malignant tumours, a special expression pattern with increased c-Jun-survivin and attenuated c-Fos-SIRT6 levels was identified. These results reveal a regulatory network connecting stress response and histone modification in liver tumour initiation, which could be targeted to prevent liver tumorigenesis.