文章：

打开癌症开关：多梳蛋白和三胸蛋白的相互作用

Throwing the cancer switch: reciprocal roles of polycomb and trithorax proteins

原文发布日期：2010-09-24

DOI: 10.1038/nrc2931

类型: Review Article

开放获取: 否

要点：

1. Transcriptional programmes established during embryogenesis are transmitted to daughter cells of the adult so that each cell maintains its appropriate identity, a process referred to as cellular or transcriptional memory. Loss of cellular memory can lead to the spurious transcription of oncogenes and silencing of tumour suppressors, which predisposes to cancer.
2. Polycomb group (PcG) and trithorax group (TrxG) proteins affect covalent modifications of histone tails, the position or composition of nucleosomes, as well as DNA methylation, thereby affecting chromatin structure and so transcriptional status. In general, PcG proteins repress — whereas TrxG proteins activate — gene expression.
3. Gain of PcG and loss of TrxG function occurs in various human cancers, which is consistent with the idea that tumour cells have stem-like characteristics. This concept is supported by the observation that tumour cells have gene expression profiles that are similar to that of embryonic cells.
4. The balance between PcG and TrxG proteins affects the expression of genes that induce cellular senescence — a tumour suppressive mechanism that opposes cellular proliferation.
5. PcG–TrxG-mediated chromatin dynamics affects the expression of genes that regulate apoptosis, a process that controls unscheduled cellular proliferation by inducing cell death. PcG proteins can recruit proteins that transcriptionally silence genes encoding components of the apoptotic machinery.
6. PcG–TrxG complexes function to maintain the integrity of the genome. The observation that loss of TrxG chromatin remodelling proteins predispose to cancer, even in the absence of genomic lesions, implies that modulation of PcG–TrxG function can be used to treat cancer.

要点翻译：

1. 胚胎发育过程中建立的转录程序会传递给成体的子代细胞，使得每个细胞保持其特定的身份，这一过程被称为细胞记忆或转录记忆。细胞记忆的缺失可能导致癌基因的异常转录及抑癌基因的沉默，从而增加患癌风险。
2. 多梳蛋白家族（PcG）和三胸蛋白家族（TrxG）通过影响组蛋白尾部的共价修饰、核小体的位置与组成以及DNA甲基化，进而调控染色质结构和转录状态。一般而言，PcG蛋白抑制基因表达，而TrxG蛋白激活基因表达。
3. 在多种人类癌症中观察到PcG功能增强和TrxG功能缺失，这与肿瘤细胞具有类干细胞特性的观点相符。这一概念得到了肿瘤细胞基因表达谱与胚胎细胞相似这一观察结果的支持。
4. PcG与TrxG蛋白之间的平衡影响着诱导细胞衰老（一种抑制细胞增殖的肿瘤抑制机制）的基因表达。
5. PcG-TrxG介导的染色质动态变化调控着凋亡相关基因的表达，这一过程通过诱导细胞死亡来控制异常增殖。PcG蛋白能够招募可转录沉默凋亡机制编码基因的蛋白。
6. PcG-TrxG复合物具有维持基因组完整性的功能。即使在不存在基因组损伤的情况下，TrxG染色质重塑蛋白缺失仍会增加癌症易感性，这一现象表明调控PcG-TrxG功能可用于癌症治疗。

英文摘要：

The discovery that cancer can be governed above and beyond the level of our DNA presents a new era for designing therapies that reverse the epigenetic state of a tumour cell. Understanding how altered chromatin dynamics leads to malignancy is essential for controlling tumour cells while sparing normal cells. Polycomb and trithorax group proteins are evolutionarily conserved and maintain chromatin in the 'off' or 'on' states, thereby preventing or promoting gene expression, respectively. Recent work highlights the dynamic interplay between these opposing classes of proteins, providing new avenues for understanding how these epigenetic regulators function in tumorigenesis.

摘要翻译： 

癌症可以受DNA层面之上的机制调控”这一发现，开启了通过逆转肿瘤细胞表观遗传状态来设计疗法的新时代。弄清染色质动态改变如何导致恶性转化，是实现对肿瘤细胞精准控制同时保护正常细胞的关键。Polycomb（多梳）与Trithorax（三胸）家族蛋白在进化上高度保守，它们分别将染色质维持在“关闭”或“开启”状态，从而抑制或促进基因表达。最新研究揭示了这两类拮抗蛋白之间的动态互作，为理解这些表观遗传调控因子在肿瘤发生中的作用开辟了新途径。

原文链接：

Throwing the cancer switch: reciprocal roles of polycomb and trithorax proteins