TMPRS2型
Erg公司
前列腺癌
生物
ETS转录因子家族
癌症研究
色丛
癌变
下调和上调
转录因子
PTEN公司
前列腺
肿瘤转化
遗传学
基因
PI3K/AKT/mTOR通路
癌症
内科学
信号转导
医学
PCA3系列
视网膜
2019年冠状病毒病(COVID-19)
疾病
传染病(医学专业)
神经科学
作者
Rohit Bose,Wouter R. Karthaus,Joshua Armenia,Wassim Abida,Phillip J. Iaquinta,Zeda Zhang,John Wongvipat,Elizabeth V. Wasmuth,Neel Shah,Patrick Sullivan,Michael G. Doran,Ping Wang,Anna Patruno,Yilin Zhao,Deyou Zheng,Nikolaus Schultz,Charles L. Sawyers
出处
期刊:Nature
[Springer Nature]
日期:2017-06-01
卷期号:546 (7660): 671-675
被引量:76
摘要
Half of all prostate cancers are caused by the TMPRSS2-ERG gene-fusion, which enables androgens to drive expression of the normally silent E26 transformation-specific (ETS) transcription factor ERG in prostate cells. Recent genomic landscape studies of such cancers have reported recurrent point mutations and focal deletions of another ETS member, the ETS2 repressor factor ERF. Here we show these ERF mutations cause decreased protein stability and mostly occur in tumours without ERG upregulation. ERF loss recapitulates the morphological and phenotypic features of ERG gain in normal mouse prostate cells, including expansion of the androgen receptor transcriptional repertoire, and ERF has tumour suppressor activity in the same genetic background of Pten loss that yields oncogenic activity by ERG. In the more common scenario of ERG upregulation, chromatin immunoprecipitation followed by sequencing indicates that ERG inhibits the ability of ERF to bind DNA at consensus ETS sites both in normal and in cancerous prostate cells. Consistent with a competition model, ERF overexpression blocks ERG-dependent tumour growth, and ERF loss rescues TMPRSS2-ERG-positive prostate cancer cells from ERG dependency. Collectively, these data provide evidence that the oncogenicity of ERG is mediated, in part, by competition with ERF and they raise the larger question of whether other gain-of-function oncogenic transcription factors might also inactivate endogenous tumour suppressors.
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