Journal
GENES & DEVELOPMENT
Volume 27, Issue 6, Pages 654-669Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.212662.112
Keywords
glioblastoma; epigenetics; DNA methylation; reprogramming; neural stem cell
Categories
Funding
- Wellcome Trust [084071]
- EMBL
- Cancer Research UK [C25858/A9160]
- EMBO Long-Term Fellowships
- Royal Society Wolfson Research Merit Award
- Swedish Research Council
- Wenner-Gren foundation
- Wellcome Beit Memorial research fellowship
- Alex Bolt research fellowship
- Brain Tumour Charity [8/105]
- MRC [G108/507, G1001028] Funding Source: UKRI
- Cancer Research UK [15155] Funding Source: researchfish
- Medical Research Council [MC_PC_12009, G1001028, G1100526, G108/507] Funding Source: researchfish
- The Brain Tumour Charity [8/105] Funding Source: researchfish
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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.
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