A Loss of Epigenetic Control Can Promote Cell Death through Reversing the Balance of Pathways in a Signaling Network.
A Loss of Epigenetic Control Can Promote Cell Death through Reversing the Balance of Pathways in a Signaling Network.
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DOI：
10.1016/j.molcel.2018.08.025
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发表时间：
2018-10-04
期刊：
影响因子：
16
通讯作者：
Levchenko A
中科院分区：
文献类型：
--
作者：
Vanaja KG;Timp W;Feinberg AP;Levchenko A
调控网络的表观遗传控制仅被部分理解。胰岛素样生长因子ii （IGF2）的表达受基因组印记控制，由母体等位基因沉默介导。IGF2 （LOI）印记缺失与肠道和结直肠癌有关，在小鼠模型中存在因果关系，在人类中存在流行病学意义。然而，LOI表型的分子基础尚不清楚。令人惊讶的是，在LOI细胞中，我们发现IGF2触发的两种典型信号通路的相对活性逆转，导致促凋亡和抗凋亡信号通路之间的进一步再平衡。预测数学模型表明，这种网络再平衡定量地解释了WT和LOI细胞中受体酪氨酸激酶抑制的影响。这一机制也定量地解释了稳定的LOI表型和选择性杀死LOI细胞的治疗窗口，从而预防表观遗传控制的癌症。这些发现为理解表观遗传修饰细胞信号提供了一个框架。
Epigenetic control of regulatory networks is only partially understood. Expression of Insulin-like growth factor-II (IGF2) is controlled by genomic imprinting, mediated by silencing of the maternal allele. Loss of imprinting of IGF2 (LOI) is linked to intestinal and colorectal cancers, causally in murine models and epidemiologically in humans. However, the molecular underpinnings of the LOI phenotype are not clear. Surprisingly, in LOI cells, we find a reversal of the relative activities of two canonical signaling pathways triggered by IGF2, causing further rebalancing between pro- and anti-apoptotic signaling. A predictive mathematical model shows that this network rebalancing quantitatively accounts for the effect of receptor tyrosine kinase inhibition in both WT and LOI cells. This mechanism also quantitatively explains both the stable LOI phenotype and the therapeutic window for selective killing of LOI cells, and thus, prevention of epigenetically controlled cancers. These findings suggest a framework for understanding epigenetically modified cell signaling.
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