Deregulation of the FOXM1 target gene network and its coregulatory partners in oesophageal adenocarcinoma.
Deregulation of the FOXM1 target gene network and its coregulatory partners in oesophageal adenocarcinoma.
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DOI：
10.1186/s12943-015-0339-8
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发表时间：
2015-03-26
期刊：
影响因子：
37.3
通讯作者：
Ang YS
中科院分区：
文献类型：
--
作者：
Wiseman EF;Chen X;Han N;Webber A;Ji Z;Sharrocks AD;Ang YS
食管腺癌（OAC）的生存率仍然很低，目前的常规治疗方式对长期生存的影响很小。这部分是由于缺乏对这种疾病中发生的分子变化的了解。先前的研究表明，转录因子FOXM1在这种癌症类型中普遍上调，但这种过表达对OAC背景下基因表达的影响在很大程度上是未知的。FOXM1不是单独起作用，而是与拮抗共调控的MMB和DREAM复合体一起起作用。为了确定FOXM1如何影响OAC中的基因表达，我们使用ChIP-seq技术鉴定了OAC衍生细胞中的FOXM1靶基因网络，并使用Nanostring基因表达试验通过数字转录计数确定了其协同调控伙伴和该靶基因网络成员在OAC中的表达。我们发现FOXM1与其靶基因网络在OAC中共同上调。此外，我们发现其共调控伙伴的表达发生了变化，包括LIN9的共同上调和令人惊讶的LIN54的表达降低。在机制上，我们确定LIN9是MMB复合体中FOXM1的直接结合伙伴。在OAC的情况下，共同调节因子（如LIN54）和靶基因（如UHRF1）的表达水平可预测疾病分期。总之，我们的数据表明，在OAC中FOXM1调控网络存在全局变化，该网络组分的表达有助于预测癌症预后。本文的在线版本（doi:10.1186/s12943-015-0339-8）包含补充材料，仅供授权用户使用。
Survival rates for oesophageal adenocarcinoma (OAC) remain disappointingly poor and current conventional treatment modalities have minimal impact on long-term survival. This is partly due to a lack of understanding of the molecular changes that occur in this disease. Previous studies have indicated that the transcription factor FOXM1 is commonly upregulated in this cancer type but the impact of this overexpression on gene expression in the context of OAC is largely unknown. FOXM1 does not function alone but works alongside the antagonistically-functioning co-regulatory MMB and DREAM complexes. To establish how FOXM1 affects gene expression in OAC we have identified the FOXM1 target gene network in OAC-derived cells using ChIP-seq and determined the expression of both its coregulatory partners and members of this target gene network in OAC by digital transcript counting using the Nanostring gene expression assay. We find co-upregulation of FOXM1 with its target gene network in OAC. Furthermore, we find changes in the expression of its coregulatory partners, including co-upregulation of LIN9 and, surprisingly, reduced expression of LIN54. Mechanistically, we identify LIN9 as the direct binding partner for FOXM1 in the MMB complex. In the context of OAC, both coregulator (eg LIN54) and target gene (eg UHRF1) expression levels are predictive of disease stage. Together our data demonstrate that there are global changes to the FOXM1 regulatory network in OAC and the expression of components of this network help predict cancer prognosis. The online version of this article (doi:10.1186/s12943-015-0339-8) contains supplementary material, which is available to authorized users.
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