文章：

实体肿瘤中的ETS家族致癌转录因子

The ETS family of oncogenic transcription factors in solid tumours

原文发布日期：2017-04-28

DOI: 10.1038/nrc.2017.20

类型: Review Article

开放获取: 否

要点：

1. ETS factor expression is aberrantly upregulated in solid tumours through chromosomal translocation and amplification.
2. Activating mutations in KIT stabilize the ETV1 protein through the MEK–ERK pathway, thus driving an oncogenic transcriptional programme in gastrointestinal stromal tumours.
3. Disruption of constitutive photomorphogenesis protein 1 (COP1)-mediated proteasomal degradation of ETS factors increases their protein stability and subsequent transcriptional activity in prostate and breast cancers.
4. Mutations in the telomerase reverse transcriptase (TERT) promoter that generate an ETS-binding site are emerging as among the most frequent mutations in solid tumours.
5. Gain of function cis-acting mutations in p53 (p53-GOF mutants) result in ETS2 protein–protein interactions and altered target gene expression affecting tumour growth, metastasis and chemotherapeutic resistance.
6. ETS factors mediate lineage specification altering stem and progenitor populations in multiple cancer types.
7. ETS fusion proteins interact with poly(ADP-ribose) polymerase 1 (PARP1) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs), both of which are mediators of DNA repair and genomic stability.
8. ETS2 functions with p53-GOF mutants to epigenetically regulate super-enhancers.
9. ETS factors function in both cell-autonomous and non-cell-autonomous manners in the tumour microenvironment to enhance cancer progression.
10. Therapeutic strategies targeting ETS factor biology are emerging and should translate clinically in the next decade.

要点翻译：

1. ETS因子在实体瘤中通过染色体易位和扩增异常上调表达。
2. KIT的激活突变通过MEK-ERK通路稳定ETV1蛋白，从而驱动胃肠道间质瘤中的致癌转录程序。
3. 组成型光形态发生蛋白1（COP1）介导的ETS因子蛋白酶体降解被破坏，增加了前列腺癌和乳腺癌中ETS因子的蛋白稳定性及后续转录活性。
4. 在端粒酶逆转录酶（TERT）启动子中产生ETS结合位点的突变，正成为实体瘤中最常见的突变之一。
5. p53的功能获得性顺式作用突变（p53-GOF突变体）导致ETS2蛋白-蛋白相互作用，并改变影响肿瘤生长、转移和化疗耐药性的靶基因表达。
6. ETS因子介导谱系特异性，改变多种癌症类型中的干细胞和祖细胞群体。
7. ETS融合蛋白与聚（ADP-核糖）聚合酶1（PARP1）和DNA依赖性蛋白激酶催化亚基（DNA-PKcs）相互作用，这两者都是DNA修复和基因组稳定性的介质。
8. ETS2与p53-GOF突变体共同作用，表现遗传调控超级增强子。
9. ETS因子在肿瘤微环境中以细胞自主和非细胞自主方式发挥作用，以促进癌症进展。
10. 针对ETS因子生物学的治疗策略正在兴起，并应在未来十年内转化为临床应用。

英文摘要：

Findings over the past decade have identified aberrant activation of the ETS transcription factor family throughout all stages of tumorigenesis. Specifically in solid tumours, gene rearrangement and amplification, feed-forward growth factor signalling loops, formation of gain-of-function co-regulatory complexes and novel cis-acting mutations in ETS target gene promoters can result in increased ETS activity. In turn, pro-oncogenic ETS signalling enhances tumorigenesis through a broad mechanistic toolbox that includes lineage specification and self-renewal, DNA damage and genome instability, epigenetics and metabolism. This Review discusses these different mechanisms of ETS activation and subsequent oncogenic implications, as well as the clinical utility of ETS factors.

摘要翻译： 

过去十年的研究发现，ETS转录因子家族在肿瘤发生的各个阶段均存在异常激活。在实体瘤中，基因重排与扩增、生长因子信号的正反馈环路、获得性功能共调控复合物的形成，以及ETS靶基因启动子区顺式作用元件的新发突变，均可导致ETS活性升高。促癌性ETS信号进而通过谱系定向、自我更新、DNA损伤与基因组不稳定、表观遗传重编程及代谢重编程等广泛机制加速肿瘤发生。本文综述了ETS激活的多种机制及其致癌意义，并探讨了ETS因子在临床中的应用价值。

原文链接：

The ETS family of oncogenic transcription factors in solid tumours