PRC2/ fox01介导的抑制决定了ETS癌基因在前列腺癌和尤因肉瘤中的互换性。

IF 4.7 2区 医学 Q2 CELL BIOLOGY
Nicholas F Downing, Kaitlyn M Mills, Peter C Hollenhorst
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引用次数: 0

摘要

在60-70%的前列腺癌和几乎所有的尤文氏肉瘤中,编码ETS家族转录因子的基因会因染色体重排而改变。尤文氏肉瘤重排导致ETS蛋白与rna结合蛋白EWSR1嵌合融合。前列腺癌重排可导致与野生型EWSR1相互作用的ETV1、ETV4、ETV5或ERG等ETS蛋白的异常表达,提示这些疾病之间的共同机制。在尤文氏肉瘤细胞系中,我们发现ETV1、ETV4和ETV5可以表型化EWSR1::FLI1。然而,ERG对EWSR1::FLI1敲低的拯救需要一个破坏与PRC2相互作用的ERG突变体。这表明驱动尤文氏肉瘤的EWSR1::ERG融合避免了PRC2的相互作用。然后,我们确定了内源性PRC2/ fox01复合物,并证明fox01是ERG/PRC2相互作用的桥梁。akt介导的FOXO1降解以及随后ERG/PRC2相互作用的缺失为前列腺癌中ERG与PTEN缺失的协同作用提供了一种机制。意义:这些发现表明驱动前列腺癌和尤因肉瘤的ETS转录因子利用类似的机制,因此可以通过类似的治疗方法靶向。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
PRC2/FOXO1-Mediated Repression Determines Interchangeability of ETS Oncogenes in Prostate Cancer and Ewing Sarcoma.

Genes encoding ETS family transcription factors are altered by chromosomal rearrangement in 60-70% of prostate cancers and nearly all Ewing sarcomas. Ewing sarcoma rearrangements result in chimeric fusion of ETS proteins to the RNA-binding protein EWSR1. Prostate cancer rearrangements result in aberrant expression of ETS proteins such as ETV1, ETV4, ETV5 or ERG that can interact with wild-type EWSR1, suggesting common mechanisms between these diseases. Here, we find that ETV1, ETV4, and ETV5 can phenocopy EWSR1::FLI1 in Ewing sarcoma cell lines. However, rescue of EWSR1::FLI1 knockdown by ERG requires an ERG mutant that disrupts interaction with PRC2. This suggests that EWSR1::ERG fusions that drive Ewing sarcoma avoid PRC2 interactions. We then identify an endogenous PRC2/FOXO1 complex and demonstrate that FOXO1 bridges the ERG/PRC2 interaction. AKT-mediated degradation of FOXO1 and subsequent loss of the ERG/PRC2 interaction provides a mechanism for ERG synergy with PTEN deletion in prostate cancer. Implications: These findings indicate that ETS transcription factors that drive prostate cancer and Ewing sarcoma utilize similar mechanisms and thus could be targeted by similar therapeutic approaches.

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来源期刊
Molecular Cancer Research
Molecular Cancer Research 医学-细胞生物学
CiteScore
9.90
自引率
0.00%
发文量
280
审稿时长
4-8 weeks
期刊介绍: Molecular Cancer Research publishes articles describing novel basic cancer research discoveries of broad interest to the field. Studies must be of demonstrated significance, and the journal prioritizes analyses performed at the molecular and cellular level that reveal novel mechanistic insight into pathways and processes linked to cancer risk, development, and/or progression. Areas of emphasis include all cancer-associated pathways (including cell-cycle regulation; cell death; chromatin regulation; DNA damage and repair; gene and RNA regulation; genomics; oncogenes and tumor suppressors; signal transduction; and tumor microenvironment), in addition to studies describing new molecular mechanisms and interactions that support cancer phenotypes. For full consideration, primary research submissions must provide significant novel insight into existing pathway functions or address new hypotheses associated with cancer-relevant biologic questions.
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