文章：

癌症中基础RNA聚合酶转录装置的失调

Dysregulation of the basal RNA polymerase transcription apparatus in cancer

原文发布日期：2013-04-24

DOI: 10.1038/nrc3496

类型: Review Article

开放获取: 否

要点：

1. The core RNA polymerase (Pol) subunits and general transcription factors (GTFs) are rarely mutated in cancer, although some GTFs are consistently overexpressed in tumours and this is thought to contribute to malignancy in some cases.
2. Subunits of the mediator complex are increasingly being found to be mutated or amplified in tumours, where they have oncogenic or tumour suppressive activities and functions, depending on the genetic background and cellular context.
3. Regulators of post-initiation stages of transcription, particularly components of RNA Pol II super elongation complexes (SECs), are recurrently mutated in cancer, particularly haematological malignancies through translocation with the mixed lineage leukaemia (MLL) family of transcription factors. The resultant fusion proteins facilitate the enhanced transcription elongation of homeobox (HOX) transcription factors that are involved in embryonic development and haematopoietic cell differentiation, which drives malignancy.
4. RNA Pol I and RNA Pol III are consistently dysregulated in cancer, which is mostly mediated through upstream oncogenic and tumour suppressive signalling pathways rather than through mutations.
5. The most potent and pervasive oncogenic and tumour suppressive components of the transcription apparatus seem to be those that are capable of modulating all three RNA Pols.
6. RNA Pol I transcriptional overactivity has been shown to be necessary for the survival of haematological tumour cells, and the RNA Pol I GTF SL-1 has been successfully targeted using a small-molecule inhibitor to therapeutically treat transgenic mouse models of cancer in vivo. RNA Pol I transcription therapy is currently entering Phase I trials in humans for the treatment of lymphoma and leukaemia.
7. Components of the core transcription apparatus, including the mediator complex and the SEC, represent bone fide therapeutic targets for cancer treatment not only as advanced broad-spectrum cytotoxics but also potentially as part of the new paradigm of personalized medicine.

要点翻译：

1. 核心RNA聚合酶（Pol）亚基和通用转录因子（GTFs）在癌症中很少发生突变，尽管一些GTFs在肿瘤中持续过表达，这被认为在某些情况下促进了恶性肿瘤的发生。
2. 中介体复合物的亚基越来越多地被发现在肿瘤中发生突变或扩增，根据遗传背景和细胞环境的不同，它们具有致癌或抑癌的活性和功能。
3. 转录起始后阶段的调控因子，特别是RNA Pol II超级延伸复合物（SECs）的组成部分，在癌症中经常发生突变，尤其是在血液系统恶性肿瘤中，通过与混合谱系白血病（MLL）转录因子家族发生易位。由此产生的融合蛋白促进了参与胚胎发育和造血细胞分化的同源盒（HOX）转录因子的转录延伸增强，从而驱动恶性肿瘤的发生。
4. RNA Pol I和RNA Pol III在癌症中持续失调，这主要是通过上游的致癌和抑癌信号通路介导的，而不是通过突变。
5. 转录装置中最有效和最普遍的致癌和抑癌成分似乎是那些能够调节所有三种RNA Pols的成分。
6. RNA Pol I转录过度活跃已被证明是血液肿瘤细胞存活所必需的，并且RNA Pol I GTF SL-1已通过小分子抑制剂成功靶向，用于在体内治疗转基因小鼠癌症模型。RNA Pol I转录疗法目前正在进入人类I期试验，用于治疗淋巴瘤和白血病。
7. 核心转录装置的组成部分，包括中介体复合物和SEC，代表了癌症治疗的真正治疗靶点，不仅作为先进的广谱细胞毒性药物，还可能作为个性化医疗新范式的一部分。

英文摘要：

Mutations that directly affect transcription by RNA polymerases rank among the most central mediators of malignant transformation, but the frequency of new anticancer drugs that selectively target defective transcription apparatus entering the clinic has been limited. This is because targeting the large protein–protein and protein–DNA interfaces that control both generic and selective aspects of RNA polymerase transcription has proved extremely difficult. However, recent technological advances have led to a 'quantum leap' in our comprehension of the structure and function of the core RNA polymerase components, how they are dysregulated in a broad range of cancers and how they may be targeted for 'transcription therapy'.

摘要翻译： 

直接影响RNA聚合酶转录的突变是最核心的恶性转化介导因素之一，但能够选择性靶向缺陷转录装置并进入临床的新型抗癌药物却寥寥无几。这是因为，控制RNA聚合酶转录的通用和选择性环节的大型蛋白-蛋白及蛋白-DNA界面极难靶向。然而，最新技术突破使我们对核心RNA聚合酶组分的结构与功能、其在多种癌症中的失调机制以及如何用于“转录治疗”有了“飞跃式”认识。

原文链接：

Dysregulation of the basal RNA polymerase transcription apparatus in cancer