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EPS8 upregulates FOXM1 expression, enhancing cell growth and motility
Huixin Wang1, Muy-Teck Teh, Youngmi Ji
1Philips Institute of Oral and Craniofacial Molecular Biology, Virginia Commonwealth University, 521 N. 11th Street, Richmond, VA 23298-0566, USA.
Carcinogenesis
|March 31, 2010
Summary
Epidermal growth factor receptor pathway substrate 8 (EPS8) enhances cell proliferation and migration by upregulating the transcription factor FOXM1 and CXC-chemokines, involving PI3K/AKT signaling pathways.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- Previous studies indicated epidermal growth factor receptor pathway substrate 8 (EPS8) overexpression enhances cell proliferation, migration, and tumorigenicity.
- The underlying molecular mechanisms of EPS8's function remained largely unexplored.
Purpose of the Study:
- To elucidate the mechanisms by which EPS8 influences cell proliferation and migration.
- To identify key mediators regulated by EPS8.
Main Methods:
- Microarray analysis to identify EPS8-regulated genes.
- Gene expression analysis, including FOXM1 and its downstream targets.
- Chromatin immunoprecipitation (ChIP) assays to assess histone modifications at the FOXM1 promoter.
- Pharmacological inhibition of PI3K/AKT pathways.
- Reporter gene assays and cell migration assays.
Main Results:
- EPS8 overexpression upregulated cell cycle regulators like FOXM1 and matrix metalloproteinase-9.
- EPS8 enhanced FOXM1 promoter activity and increased histone H3 acetylation at the FOXM1 promoter.
- PI3K/AKT pathway inhibition reduced FOXM1 and aurora-B kinase expression.
- EPS8 induced CXCL5 and CXCL12 expression in a FOXM1-dependent and PI3K/AKT-mediated manner.
- FOXM1 overexpression enhanced cell migration, while CXCL5 knockdown or AKT inhibition reduced migration in EPS8-expressing cells.
Conclusions:
- EPS8 promotes cell proliferation and migration partly through deregulation of FOXM1 activity.
- EPS8 induces CXC-chemokine expression via PI3K- and AKT-dependent pathways.
- These findings reveal a novel signaling axis involving EPS8, FOXM1, and CXC-chemokines in cancer progression.
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