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ERF mutations reveal a balance of ETS factors controlling prostate oncogenesis

机译:ERF突变揭示了控制前列腺癌发生的ETS因子平衡

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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(1,2). Recent genomic landscape studies of such cancers3-8 have reported recurrent point mutations and focal deletions of another ETS member, the ETS2 repressor factor ERF9. 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.
机译:所有前列腺癌的一半是由TMPRSS2-ERG基因融合引起的,它使雄激素能够驱动通常沉默的E26转化特异性(ETS)转录因子ERG在前列腺细胞中的表达(1,2)。最近对这类癌症的基因组研究3-8报告了另一种ETS成员ETS2阻遏因子ERF9的复发点突变和灶性缺失。在这里,我们显示这些ERF突变会导致蛋白质稳定性下降,并且大多数发生在没有ERG上调的肿瘤中。 ERF丧失概括了正常小鼠前列腺细胞中ERG获得的形态和表型特征,包括雄激素受体转录谱的扩展,并且ERF在Pten丧失的相同遗传背景中具有肿瘤抑制活性,而ETEN产生了致癌活性。在更常见的ERG上调情况下,染色质免疫沉淀后再测序表明ERG在正常和癌性前列腺细胞中均抑制ERF结合共有ETS位点上的DNA的能力。与竞争模型一致,ERF的过表达会阻止ERG依赖性肿瘤的生长,而ERF的丧失则可从ERG依赖性中拯救TMPRSS2-ERG阳性前列腺癌细胞。总体而言,这些数据提供了证据,证明ERG的致癌性部分是由与ERF的竞争介导的,它们提出了一个更大的问题,即其他功能获得性致癌转录因子是否也可能使内源性肿瘤抑制因子失活。

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  • 来源
    《Nature》 |2017年第7660期|671-675|共5页
  • 作者单位

    Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10065 USA|Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10065 USA;

    Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10065 USA;

    Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10065 USA|Mem Sloan Kettering Canc Ctr, Ctr Mol Oncol, 1275 York Ave, New York, NY 10065 USA;

    Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10065 USA;

    Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10065 USA;

    Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10065 USA|Mem Sloan Kettering Canc Ctr, Louis V Gerstner Jr Grad Sch Biomed Sci, New York, NY 10065 USA;

    Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10065 USA;

    Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10065 USA;

    Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10065 USA;

    Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10065 USA;

    Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10065 USA;

    Albert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USA;

    Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10065 USA;

    Albert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USA;

    Albert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USA|Albert Einstein Coll Med, Dept Neurol, Bronx, NY 10461 USA|Albert Einstein Coll Med, Dept Neurosci, Bronx, NY 10461 USA;

    Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10065 USA|Mem Sloan Kettering Canc Ctr, Ctr Mol Oncol, 1275 York Ave, New York, NY 10065 USA;

    Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10065 USA|Howard Hughes Med Inst, Chevy Chase, MD 20185 USA;

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