Deregulation of the FOXM1 target gene network and its coregulatory partners in oesophageal adenocarcinoma

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• 作者：Elizabeth F Wiseman (1) (2)
  Xi Chen (1) (3)
  Namshik Han (1) (4)
  Aaron Webber (1)
  Zongling Ji (1)
  Andrew D Sharrocks (1)
  Yeng S Ang (2)
  
  1. Faculty of Life Sciences ; University of Manchester ; Michael Smith Building ; Oxford Road ; Manchester ; M13 9PT ; UK
  2. Faculty of Medical and Human Sciences ; University of Manchester ; Oxford Road ; Manchester ; UK
  3. Present address ; The EMBL-European Bioinformatics Institute ; Wellcome Trust Genome Campus ; Hinxton ; Cambridge ; CB10 1SD ; UK
  4. Present address ; Gurdon Institute and Department of Pathology ; Tennis Court Road ; Cambridge ; CB2 1QN ; UK
  
• 关键词：FOXM1 ; MMB complex ; G2 ; M cell cycle phase ; Oesophageal adenocarcinoma
• 刊名：Molecular Cancer
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：14
• 期：1
• 全文大小：2,552 KB
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• 刊物主题：Cancer Research; Oncology;
• 出版者：BioMed Central
• ISSN：1476-4598

文摘

Background 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. Methods 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. Results 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. Conclusions 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.