ETS Transcription Factor ESE1/ELF3 Orchestrates a Positive Feedback Loop That Constitutively Activates NF-κB and Drives Prostate Cancer Progression
ETS Transcription Factor ESE1/ELF3 Orchestrates a Positive Feedback Loop That Constitutively Activates NF-κB and Drives Prostate Cancer Progression
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DOI：
10.1158/0008-5472.can-12-4537
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发表时间：
2013-07-15
期刊：
影响因子：
11.2
通讯作者：
Carbone, Giuseppina M.
中科院分区：
文献类型：
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作者：
Longoni, Nicole;Sarti, Manuela;Carbone, Giuseppina M.
染色体易位导致ETS转录因子表达失调在前列腺肿瘤中很常见。在这里，我们报告了一种新的机制，导致致癌激活的ETS因子ESE 1/ELF 3在前列腺肿瘤。ESE 1/ELF 3在人类原发性和转移性肿瘤中过表达。它在体外和体内介导转化表型，并诱导炎性转录物组与相关致癌途径的变化。NSE 1/ELF 3由白细胞介素（IL）-1 β通过NF-κ B诱导，并且是前列腺癌细胞中由IL-1 β诱导的表型和转录变化的关键介质。这种连接是通过ESE 1/ELF 3与NF-κ B亚基p65和p50的相互作用介导的，通过增强它们的核转位和转录活性以及通过诱导p50转录起作用。支持这些发现的是，基因表达谱揭示了在表达高水平ESE 1/ELF 3的前列腺癌细胞或肿瘤中NF-κ B效应子功能的富集。我们观察到人前列腺肿瘤中NSE 1/ELF 3和NF-κ B的一致上调与不良预后相关。总的来说，我们的研究结果定义了炎症信号与前列腺癌进展之间重要的新机制联系。
Chromosomal translocations leading to deregulated expression of ETS transcription factors are frequent in prostate tumors. Here, we report a novel mechanism leading to oncogenic activation of the ETS factor ESE1/ELF3 in prostate tumors. ESE1/ELF3 was overexpressed in human primary and metastatic tumors. It mediated transforming phenotypes in vitro and in vivo and induced an inflammatory transcriptome with changes in relevant oncogenic pathways. ESE1/ELF3 was induced by interleukin (IL)-1 beta through NF-kappa B and was a crucial mediator of the phenotypic and transcriptional changes induced by IL-1 beta in prostate cancer cells. This linkage was mediated by interaction of ESE1/ELF3 with the NF-kappa B subunits p65 and p50, acting by enhancing their nuclear translocation and transcriptional activity and by inducing p50 transcription. Supporting these findings, gene expression profiling revealed an enrichment of NF-kappa B effector functions in prostate cancer cells or tumors expressing high levels of ESE1/ELF3. We observed concordant upregulation of ESE1/ELF3 and NF-kappa B in human prostate tumors that was associated with adverse prognosis. Collectively, our results define an important new mechanistic link between inflammatory signaling and the progression of prostate cancer.