Identification of Global DNA Methylation Signatures in Glioblastoma-Derived Cancer Stem Cells

a.
GRU Cancer Center, Georgia Regents University, Augusta, GA 30912, USA
b.
Department of Biology, College of Art and Sciences, University of Missouri, Columbia, MO 65211, USA
c.
Department of Biochemistry and Molecular Biology, Georgia Regents University, Augusta, GA 30912, USA
d.
Division of Neurological Surgery, University of Missouri School of Medicine, Columbia, MO 65211, USA
e.
Department of Pathology and Anatomical Sciences, University of Missouri School of Medicine, Columbia, MO 65211, USA
f.
Department of Pathology and Laboratory Medicine, Brown University and Lifespan Academic Medical Center, Providence, RI 02903, USA
g.
Department of Neurology, The Hugo W. Moser Research Institute at Kennedy Krieger Inc. and The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
h.
Institute of Translational Medicine, Nanchang University, Nanchang 330031, China
i.
David H. Murdock Research Institute, Kannapolis, NC 28081, USA
j.
Department of Biostatistics and Epidemiology, Georgia Regents University, Augusta, GA 30912, USA

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Corresponding author: E-mail address: jechoi@gru.edu (Jeong-Hyeon Choi); E-mail address: hshi@gru.edu (Huidong Shi)

These authors contributed equally to this work.

摘要

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Abstract: Glioblastoma (GBM) is the most common and most aggressive primary brain tumor in adults. The existence of a small population of stem-like tumor cells that efficiently propagate tumors and resist cytotoxic therapy is one proposed mechanism leading to the resilient behavior of tumor cells and poor prognosis. In this study, we performed an in-depth analysis of the DNA methylation landscape in GBM-derived cancer stem cells (GSCs). Parallel comparisons of primary tumors and GSC lines derived from these tumors with normal controls (a neural stem cell (NSC) line and normal brain tissue) identified groups of hyper- and hypomethylated genes that display a trend of either increasing or decreasing methylation levels in the order of controls, primary GBMs, and their counterpart GSC lines, respectively. Interestingly, concurrent promoter hypermethylation and gene body hypomethylation were observed in a subset of genes including MGMT, AJAP1 and PTPRN2. These unique DNA methylation signatures were also found in primary GBM-derived xenograft tumors indicating that they are not tissue culture-related epigenetic changes. Integration of GSC-specific epigenetic signatures with gene expression analysis further identified candidate tumor suppressor genes that are frequently down-regulated in GBMs such asSPINT2, NEFM and PENK. Forced re-expression of SPINT2 reduced glioma cell proliferative capacity, anchorage independent growth, cell motility, and tumor sphere formation in vitro. The results from this study demonstrate that GSCs possess unique epigenetic signatures that may play important roles in the pathogenesis of GBM.
- Glioblastoma /
- Cancer stem cells /
- DNA methylation /
- SPINT2
These authors contributed equally to this work.
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doi: 10.1016/j.jgg.2015.06.003

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Identification of Global DNA Methylation Signatures in Glioblastoma-Derived Cancer Stem Cells

Corresponding author: E-mail address: jechoi@gru.edu (Jeong-Hyeon Choi); E-mail address: hshi@gru.edu (Huidong Shi)

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doi: 10.1016/j.jgg.2015.06.003

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Identification of Global DNA Methylation Signatures in Glioblastoma-Derived Cancer Stem Cells

Corresponding author: E-mail address: jechoi@gru.edu (Jeong-Hyeon Choi); E-mail address: hshi@gru.edu (Huidong Shi)

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