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Widespread resetting of DNA methylation in glioblastoma-initiating cells suppresses malignant cellular behavior in a lineage-dependent manner.

TitleWidespread resetting of DNA methylation in glioblastoma-initiating cells suppresses malignant cellular behavior in a lineage-dependent manner.
Publication TypeJournal Article
Year of Publication2013
AuthorsStricker SH, Feber A, Engström PG, Carén H, Kurian KM, Takashima Y, Watts C, Way M, Dirks P, Bertone P, Smith A, Beck S, Pollard SM
JournalGenes Dev
Volume27
Issue6
Pagination654-69
Date Published2013 Mar 15
ISSN1549-5477
KeywordsAnimals, Cell Differentiation, Cell Line, Tumor, Cell Lineage, Cell Transformation, Neoplastic, DNA Methylation, Epigenesis, Genetic, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Glioblastoma, Humans, Mice, Mice, Inbred NOD, Neural Stem Cells, Nuclear Reprogramming, Pluripotent Stem Cells, Transplantation, Heterologous
Abstract

Epigenetic changes are frequently observed in cancer. However, their role in establishing or sustaining the malignant state has been difficult to determine due to the lack of experimental tools that enable resetting of epigenetic abnormalities. To address this, we applied induced pluripotent stem cell (iPSC) reprogramming techniques to invoke widespread epigenetic resetting of glioblastoma (GBM)-derived neural stem (GNS) cells. GBM iPSCs (GiPSCs) were subsequently redifferentiated to the neural lineage to assess the impact of cancer-specific epigenetic abnormalities on tumorigenicity. GiPSCs and their differentiating derivatives display widespread resetting of common GBM-associated changes, such as DNA hypermethylation of promoter regions of the cell motility regulator TES (testis-derived transcript), the tumor suppressor cyclin-dependent kinase inhibitor 1C (CDKN1C; p57KIP2), and many polycomb-repressive complex 2 (PRC2) target genes (e.g., SFRP2). Surprisingly, despite such global epigenetic reconfiguration, GiPSC-derived neural progenitors remained highly malignant upon xenotransplantation. Only when GiPSCs were directed to nonneural cell types did we observe sustained expression of reactivated tumor suppressors and reduced infiltrative behavior. These data suggest that imposing an epigenome associated with an alternative developmental lineage can suppress malignant behavior. However, in the context of the neural lineage, widespread resetting of GBM-associated epigenetic abnormalities is not sufficient to override the cancer genome.

DOI10.1101/gad.212662.112
Alternate JournalGenes Dev.
PubMed ID23512659
PubMed Central IDPMC3613612
Grant List079249 / / Wellcome Trust / United Kingdom
084071 / / Wellcome Trust / United Kingdom
C25858/A9160 / / Cancer Research UK / United Kingdom
G108/507 / / Medical Research Council / United Kingdom
G1100526 / / Medical Research Council / United Kingdom
/ / Medical Research Council / United Kingdom
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