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Mol Cancer Res. 2017 Aug;15(8):998-1011. doi: 10.1158/1541-7786.MCR-16-0494. Epub 2017 May 16.

Epigenetic Regulation of ZBTB18 Promotes Glioblastoma Progression.

Author information

1
Department of Neurosurgery, Medical Center, University of Freiburg, Freiburg, Germany.
2
Faculty of Medicine, University of Freiburg, Freiburg, Germany.
3
Institute of Neuropathology, Neurocenter, and Comprehensive Cancer Center, University of Freiburg, Freiburg, Germany.
4
BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
5
The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut.
6
Department of Immunology, Genetics and Pathology and Science for Life Laboratories, University of Uppsala, Uppsala, Sweden.
7
Institute for Cancer Genetics, Columbia University, New York, New York.
8
Department of Biomedical Informatics, Columbia University, New York, New York.
9
Department of Systems Biology, Columbia University, New York, New York.
10
Department of Pathology, Columbia University Medical Center, New York, New York.
11
Department of Neurology, Columbia University Medical Center, New York, New York.
12
Department of Radiation Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama.
13
Department of Neurosurgery, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.
14
Department of Neurosurgery, Medical Center, University of Freiburg, Freiburg, Germany. maria.carro@uniklinik-freiburg.de.

Abstract

Glioblastoma (GBM) comprises distinct subtypes characterized by their molecular profile. Mesenchymal identity in GBM has been associated with a comparatively unfavorable prognosis, primarily due to inherent resistance of these tumors to current therapies. The identification of molecular determinants of mesenchymal transformation could potentially allow for the discovery of new therapeutic targets. Zinc Finger and BTB Domain Containing 18 (ZBTB18/ZNF238/RP58) is a zinc finger transcriptional repressor with a crucial role in brain development and neuronal differentiation. Here, ZBTB18 is primarily silenced in the mesenchymal subtype of GBM through aberrant promoter methylation. Loss of ZBTB18 contributes to the aggressive phenotype of glioblastoma through regulation of poor prognosis-associated signatures. Restitution of ZBTB18 expression reverses the phenotype and impairs tumor-forming ability. These results indicate that ZBTB18 functions as a tumor suppressor in GBM through the regulation of genes associated with phenotypically aggressive properties.Implications: This study characterizes the role of the putative tumor suppressor ZBTB18 and its regulation by promoter hypermethylation, which appears to be a common mechanism to silence ZBTB18 in the mesenchymal subtype of GBM and provides a new mechanistic opportunity to specifically target this tumor subclass. Mol Cancer Res; 15(8); 998-1011. ©2017 AACR.

PMID:
28512252
PMCID:
PMC5967621
DOI:
10.1158/1541-7786.MCR-16-0494
[Indexed for MEDLINE]
Free PMC Article

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