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PMID: 23818228 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

The ZEB1 pathway links glioblastoma initiation, invasion and chemoresistance.

EMBO molecular medicine ·Vol. 5 ·No. 8 ·2013-08-00 ·Pages 1196-212

Siebzehnrubl FA, Silver DJ, Tugertimur B, Deleyrolle LP, Siebzehnrubl D, Sarkisian MR, Devers KG, Yachnis AT, Kupper MD, Neal D, Nabilsi NH, Kladde MP, Suslov O, Brabletz S, Brabletz T, Reynolds BA, Steindler DA

Abstract

Glioblastoma remains one of the most lethal types of cancer, and is the most common brain tumour in adults. In particular, tumour recurrence after surgical resection and radiation invariably occurs regardless of aggressive chemotherapy. Here, we provide evidence that the transcription factor ZEB1 (zinc finger E-box binding homeobox 1) exerts simultaneous influence over invasion, chemoresistance and tumourigenesis in glioblastoma. ZEB1 is preferentially expressed in invasive glioblastoma cells, where the ZEB1-miR-200 feedback loop interconnects these processes through the downstream effectors ROBO1, c-MYB and MGMT. Moreover, ZEB1 expression in glioblastoma patients is predictive of shorter survival and poor Temozolomide response. Our findings indicate that this regulator of epithelial-mesenchymal transition orchestrates key features of cancer stem cells in malignant glioma and identify ROBO1, OLIG2, CD133 and MGMT as novel targets of the ZEB1 pathway. Thus, ZEB1 is an important candidate molecule for glioblastoma recurrence, a marker of invasive tumour cells and a potential therapeutic target, along with its downstream effectors.

Keywords
EMT brain cancer stem cell glioma xenograft
MeSH Terms
Animals Antineoplastic Agents/pharmacology Brain Neoplasms/drug therapy,metabolism Cell Line, Tumor Cell Survival DNA Modification Methylases/metabolism DNA Repair Enzymes/metabolism Dacarbazine/analogs & derivatives,pharmacology Drug Resistance, Neoplasm Female Gene Expression Regulation, Neoplastic Glioblastoma/drug therapy,metabolism Homeodomain Proteins/metabolism Humans Kruppel-Like Transcription Factors/metabolism Mice Mice, SCID Neoplasm Invasiveness Neoplasm Transplantation Nerve Tissue Proteins/metabolism Proto-Oncogene Proteins c-myb/metabolism Receptors, Immunologic/metabolism Temozolomide Transcription Factors/metabolism Treatment Outcome Tumor Suppressor Proteins/metabolism Zinc Finger E-box-Binding Homeobox 1
Chemicals
Antineoplastic Agents Homeodomain Proteins Kruppel-Like Transcription Factors Nerve Tissue Proteins Proto-Oncogene Proteins c-myb Receptors, Immunologic Transcription Factors Tumor Suppressor Proteins ZEB1 protein, human ZEB1 protein, mouse Zinc Finger E-box-Binding Homeobox 1 roundabout protein Dacarbazine DNA Modification Methylases MGMT protein, human DNA Repair Enzymes Temozolomide
Authors & Affiliations
17 authors, click to expand affiliations / ORCID
Siebzehnrubl Florian A
Department of Neurosurgery, University of Florida, Gainesville, FL, USA. fas@ufl.edu
Silver Daniel J
Tugertimur Bugra
Deleyrolle Loic P
Siebzehnrubl Dorit
Sarkisian Matthew R
Devers Kelly G
Yachnis Antony T
Kupper Marius D
Neal Daniel
Nabilsi Nancy H
Kladde Michael P
Suslov Oleg
Brabletz Simone
Brabletz Thomas
Reynolds Brent A
Steindler Dennis A
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Article Info
Journal
EMBO molecular medicine
Abbr.
EMBO Mol Med
ISSN
1757-4684
DOI
10.1002/emmm.201302827
Email
fas@ufl.edu
Published
2013-08-00
Epub
2013-00-01
Pages
1196-212
Language
English
Region
England
NLM ID
101487380
PMCID
PMC3944461
Subset
IM
Grants
NCI NIH HHS · R21 CA141020 · United States
NCI NIH HHS · R01 CA155390 · United States
NINDS NIH HHS · NS055165 · United States
NINDS NIH HHS · R01 NS055165 · United States
NCI NIH HHS · CA141020 · United States
External Links
PubMed source DOI: 10.1002/emmm.201302827 PMC Full Text View journal details
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