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Research Watch

Reversible Epigenetic Changes Create Refractory Glioblastoma Stem Cells

DOI: 10.1158/2159-8290.CD-RW2016-240 Published February 2017
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  • Major finding: RTK inhibitors induce glioblastoma stem cells (GSC) to transition to a slow-cycling persister state.

  • Mechanism: KDM6 removes repressive H3K27me3 to upregulate Notch and neurodevelopmental genes in persister GSCs.

  • Impact: The epigenetic mechanism underlying persister GSC establishment may be targetable in glioblastoma.

Despite frequent alterations in receptor tyrosine kinases (RTK), RTK inhibitors have limited clinical efficacy in patients with glioblastoma, likely due to a subpopulation of refractory slow-cycling glioblastoma stem-like cells (GSC). Liau, Sievers, and colleagues investigated the molecular mechanisms underlying the therapeutic resistance of GSCs. In GSC cell lines, treatment with the RTK inhibitor dasatinib rapidly enriched a drug-tolerant, slow-cycling GSC “persister” population without evidence of genetic alterations that would confer resistance. When dasatinib was removed the cells reverted to a proliferative state, suggesting a reversible epigenetic mechanism of resistance. Compared with naïve GSCs, the persister GSCs exhibited upregulation of genes involved in primitive neurodevelopment and quiescence, consistent with a slow-cycling state, and increased Notch signaling. Small molecule–mediated inhibition of Notch activation reduced the growth of persister GSCs but had little effect on naïve GSCs, whereas overexpression of the Notch1 intracellular domain (N1ICD) induced a reversible growth reduction in the naïve GSCs, suggesting that Notch signaling promotes the switch to a slow-cycling, RTK inhibitor–resistant persister GSC phenotype. These findings were validated in primary glioblastoma tumors which harbored Notch-positive cells with low expression of proliferation markers, indicative of persister GSCs. Chromatin immunoprecipitation sequencing showed that N1ICD and its cofactor RBPJ were enriched at the enhancers of neurodevelopmental genes in persister GSCs compared with naïve GSCs. Further, N1ICD-associated loci lost H3K27me3, a repressive chromatin mark, and gained H3K27ac as they transitioned from the naïve state to the persister state. This transition was accompanied by downregulation of the H3K27 methyltransferase EZH2 and upregulation of the H3K27 demethylases KDM6A and KDM6B, and, accordingly, persister GSCs were dependent on KDM6 activity. Collectively, these results indicate that a KDM6-dependent chromatin remodeling allows a reversible transition to a drug-tolerant, slow-cycling persister GSC state. Thus, targeting epigenetic and developmental pathways may target GSCs to potentially prevent drug resistance in patients with glioblastoma.

Liau BB, Sievers C, Donohue LK, Gillespie SM, Flavahan WA, Miller TE, et al. Adaptive chromatin remodeling drives glioblastoma stem cell plasticity and drug tolerance. Cell Stem Cell 2016 Dec 15 [Epub ahead of print].

Notes

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.

  • ©2017 American Association for Cancer Research.
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Cancer Discovery: 7 (2)
February 2017
Volume 7, Issue 2
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Reversible Epigenetic Changes Create Refractory Glioblastoma Stem Cells
Cancer Discov February 1 2017 (7) (2) 124; DOI: 10.1158/2159-8290.CD-RW2016-240

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Reversible Epigenetic Changes Create Refractory Glioblastoma Stem Cells
Cancer Discov February 1 2017 (7) (2) 124; DOI: 10.1158/2159-8290.CD-RW2016-240
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