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Widespread resetting of DNA methylation in glioblastoma-initiating cells suppresses malignant cellular behavior in a lineage-dependent manner.
Stricker, Stefan H; Feber, Andrew; Engström, Pär G; Carén, Helena; Kurian, Kathreena M; Takashima, Yasuhiro; Watts, Colin; Way, Michael; Dirks, Peter; Bertone, Paul; Smith, Austin; Beck, Stephan; Pollard, Steven M.
Afiliación
  • Stricker SH; Department of Cancer Biology, UCL Cancer Institute, University College London, London WC1E 6BT, United Kingdom.
Genes Dev ; 27(6): 654-69, 2013 Mar 15.
Article en En | MEDLINE | ID: mdl-23512659
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.
Asunto(s)

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Glioblastoma / Metilación de ADN / Epigénesis Genética / Reprogramación Celular / Células-Madre Neurales Límite: Animals / Humans Idioma: En Revista: Genes Dev Asunto de la revista: BIOLOGIA MOLECULAR Año: 2013 Tipo del documento: Article País de afiliación: Reino Unido

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Glioblastoma / Metilación de ADN / Epigénesis Genética / Reprogramación Celular / Células-Madre Neurales Límite: Animals / Humans Idioma: En Revista: Genes Dev Asunto de la revista: BIOLOGIA MOLECULAR Año: 2013 Tipo del documento: Article País de afiliación: Reino Unido