Document Detail

EPS8 upregulates FOXM1 expression, enhancing cell growth and motility.
MedLine Citation:
PMID:  20351091     Owner:  NLM     Status:  MEDLINE    
Previous studies from our laboratory have indicated that overexpression of the epidermal growth factor receptor pathway substrate 8 (EPS8) enhances cell proliferation, migration and tumorigenicity in vivo, although the mechanisms involved remain unexplored. A microarray screen to search for potential mediators of EPS8 identified upregulation of multiple cell cycle-related targets such as the transcription factor FOXM1 and several of its reported downstream mediators, including cdc20, cyclin B1, cyclin A, aurora-B kinase and cdc25C in cells with elevated EPS8, as well as matrix metalloproteinase-9, which we reported previously to be upregulated by EPS8-dependent mechanisms. Cells engineered to overexpress FOXM1 showed increased proliferation, similar to EPS8-overexpressing cells. Conversely, targeted knockdown of FOXM1 in EPS8-overexpressing cells reduced proliferation. Cotransfection of EPS8 with a FOXM1-luciferase reporter plasmid into 293-T- or SVpgC2a-immortalized buccal keratinocytes demonstrated that EPS8 enhances FOXM1 promoter activity, whereas chromatin immunoprecipitation assays revealed elevated levels of acetylated histone H3 associated with the FOXM1 promoter in cells expressing high levels of EPS8. Treatment of EPS8-overexpressing cells with inhibitors of phosphoinositide 3-OH kinase or AKT reduced expression of FOXM1 and aurora-B kinase, a transcriptional target of FOXM1. Overexpression of EPS8 induced expression of the chemokine ligands CXCL5 and CXCL12 in a FOXM1-dependent manner, which was blocked by LY294002 or a dominant-negative form of AKT. Additionally, overexpression of FOXM1 enhanced cell migration, whereas targeted knockdown of CXCL5 or inhibition of AKT reduced migration of EPS8-expressing cells. These data suggest that EPS8 enhances cell proliferation and migration in part by deregulating FOXM1 activity and inducing CXC-chemokine expression, mediated by PI3K- and AKT-dependent mechanisms.
Huixin Wang; Muy-Teck Teh; Youngmi Ji; Vyomesh Patel; Shahrzad Firouzabadian; Anisha A Patel; J Silvio Gutkind; W Andrew Yeudall
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't     Date:  2010-03-29
Journal Detail:
Title:  Carcinogenesis     Volume:  31     ISSN:  1460-2180     ISO Abbreviation:  Carcinogenesis     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-05-31     Completed Date:  2010-06-24     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  8008055     Medline TA:  Carcinogenesis     Country:  England    
Other Details:
Languages:  eng     Pagination:  1132-41     Citation Subset:  IM    
Philips Institute of Oral and Craniofacial Molecular Biology, Virginia Commonwealth University, 521 N. 11th Street, Richmond, VA 23298-0566, USA.
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MeSH Terms
Adaptor Proteins, Signal Transducing
Blotting, Western
Cell Division / physiology*
Cell Line, Tumor
Cell Movement / physiology*
Chemokine CXCL5 / metabolism
Chromatin Immunoprecipitation
Forkhead Transcription Factors / genetics,  physiology*
Intracellular Signaling Peptides and Proteins / physiology*
Polymerase Chain Reaction
RNA Interference
Up-Regulation / physiology*
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/CXCL5 protein, human; 0/Chemokine CXCL5; 0/EPS8 protein, human; 0/FOXM1 protein, human; 0/Forkhead Transcription Factors; 0/Intracellular Signaling Peptides and Proteins

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