文章：

超越转录因子：致癌信号如何重塑表观遗传景观

Beyond transcription factors: how oncogenic signalling reshapes the epigenetic landscape

原文发布日期：2016-05-25

DOI: 10.1038/nrc.2016.41

类型: Review Article

开放获取: 否

要点：

1. Alterations in the epigenetic landscape are a hallmark of human cancer. Cancer-associated changes in the covalent modifications of DNA and histones may arise from mutations in, or the altered expression of, chromatin modifiers and/or non-coding RNAs. Recent studies show that the interplay between upstream signalling pathways and chromatin modifications represents an important mechanism controlling the cancer epigenome.
2. Kinase signalling pathways can modify the epigenome via direct phosphorylation of histones or chromatin modifiers, leading to changes in chromatin structure and gene expression. These pathways can be hijacked by oncogenic mutations to aberrantly modulate chromatin modifications. Oncogenic signalling pathways can also contribute to cancer-specific methylation patterns by controlling global DNA methyltransferase activity or the accessibility of certain regulatory elements to DNA methylation.
3. Histone modifications are involved in various cellular processes, including transcription activation, apoptosis, DNA repair and mitotic chromatin condensation. The dynamic process of phosphorylation (for example, at histones H3S10 and H3S28) can impair the deposition of potentially more stable methyl marks on adjacent lysine residues; such crosstalk can amplify the influence of signalling pathways on chromatin structure.
4. Chromatin modifiers, such as enhancer of zeste homologue 2 (EZH2), BMI1, p300 and CREB binding protein (CBP), are phosphorylated by multiple upstream signalling kinases, indicating that they can function as points of convergence for these signalling pathways. The end result of these phosphorylation events can vary depending on their site-specific and cell type-specific context.
5. The DNA damage response represents a major signalling pathway that alters chromatin structure via the phosphorylation of histones and histone modifiers. The decision of cells to undergo cell cycle arrest and repair damaged DNA or undergo cell death reflects the integration of various upstream signals.
6. The interplay between signalling pathways and the epigenome may have important implications for therapeutic strategies for cancer. Treating tumour cells with kinase inhibitors may not be sufficient to restore the deregulated gene expression programmes that are found in these cells. Combining kinase inhibitors with epigenetically focused therapies may more effectively reverse the epigenetic features that maintain the transformed phenotype in cancer cells, leading to improved patient outcomes.

要点翻译：

1. 表观遗传景观的改变是人类癌症的一个标志。DNA和组蛋白共价修饰中与癌症相关的变化可能源于染色质修饰因子和/或非编码RNA的突变或表达改变。近期研究表明，上游信号通路与染色质修饰之间的相互作用是控制癌症表观基因组的重要机制。
2. 激酶信号通路可通过直接磷酸化组蛋白或染色质修饰因子来改变表观基因组，从而导致染色质结构和基因表达的变化。这些通路可能被致癌突变劫持，从而异常调节染色质修饰。致癌信号通路还可通过调控全局DNA甲基转移酶活性或特定调控元件对DNA甲基化的可及性，促成癌症特异性甲基化模式。
3. 组蛋白修饰参与多种细胞过程，包括转录激活、细胞凋亡、DNA修复和有丝分裂染色质凝集。磷酸化的动态过程（例如组蛋白H3S10和H3S28位点）可能阻碍相邻赖氨酸残基上潜在更稳定甲基标记的沉积；这种交叉对话可放大信号通路对染色质结构的影响。
4. 染色质修饰因子如zeste同源物2增强子（EZH2）、BMI1、p300和CREB结合蛋白（CBP）可被多个上游信号激酶磷酸化，表明它们可作为这些信号通路的汇聚点。这些磷酸化事件的最终结果因其位点特异性和细胞类型特异性背景而有所不同。
5. DNA损伤反应是通过组蛋白和组蛋白修饰因子磷酸化改变染色质结构的主要信号通路。细胞决定进行细胞周期停滞并修复受损DNA，或走向细胞死亡，这反映了多种上游信号的整合。
6. 信号通路与表观基因组之间的相互作用可能对癌症治疗策略具有重要启示。仅用激酶抑制剂治疗肿瘤细胞可能不足以恢复这些细胞中失调的基因表达程序。将激酶抑制剂与表观遗传靶向疗法相结合，或能更有效地逆转维持癌细胞转化表型的表观遗传特征，从而改善患者预后。

英文摘要：

Cancer, once thought to be caused largely by genetic alterations, is now considered to be a mixed genetic and epigenetic disease. The epigenetic landscape, which is dictated by covalent DNA and histone modifications, is profoundly altered in transformed cells. These abnormalities may arise from mutations in, or altered expression of, chromatin modifiers. Recent reports on the interplay between cellular signalling pathways and chromatin modifications add another layer of complexity to the already complex regulation of the epigenome. In this Review, we discuss these new studies and how the insights they provide can contribute to a better understanding of the molecular pathogenesis of neoplasia.

摘要翻译： 

癌症曾被认为是主要由基因改变引起的疾病，如今则被视为一种遗传与表观遗传混合的疾病。表观遗传景观由DNA和组蛋白的共价修饰决定，在转化细胞中发生深刻改变。这些异常可能源于染色质修饰因子的突变或其表达的改变。近期关于细胞信号通路与染色质修饰相互作用的研究，为原本已十分复杂的表观基因组调控增添了新的层面。在本综述中，我们将讨论这些新研究，以及它们带来的洞见如何有助于更深入地理解肿瘤发生的分子机制。

原文链接：

Beyond transcription factors: how oncogenic signalling reshapes the epigenetic landscape