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de Vries NA, Hulsman D, Akhtar W, et al. Prolonged Ezh2 Depletion in Glioblastoma Causes a Robust Switch in Cell Fate Resulting in Tumor Progression. Cell Rep. 2015;10(3):383-397doi: 10.1016/j.celrep.2014.12.028.
de Vries, N. A., Hulsman, D., Akhtar, W., de Jong, J., Miles, D. C., Blom, M., van Tellingen, O., Jonkers, J., & van Lohuizen, M. (2015). Prolonged Ezh2 Depletion in Glioblastoma Causes a Robust Switch in Cell Fate Resulting in Tumor Progression. Cell reports, 10(3), 383-397. https://doi.org/10.1016/j.celrep.2014.12.028
de Vries, Nienke A, et al. "Prolonged Ezh2 Depletion in Glioblastoma Causes a Robust Switch in Cell Fate Resulting in Tumor Progression." Cell reports vol. 10,3 (2015): 383-397. doi: https://doi.org/10.1016/j.celrep.2014.12.028
de Vries NA, Hulsman D, Akhtar W, de Jong J, Miles DC, Blom M, van Tellingen O, Jonkers J, van Lohuizen M. Prolonged Ezh2 Depletion in Glioblastoma Causes a Robust Switch in Cell Fate Resulting in Tumor Progression. Cell Rep. 2015 Jan 20;10(3):383-397. doi: 10.1016/j.celrep.2014.12.028. Epub 2015 Jan 15. PMID: 25600873.
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Cell Rep. 2015 Jan 20;10(3):383-397. doi: 10.1016/j.celrep.2014.12.028. Epub 2015 Jan 15.

Prolonged Ezh2 Depletion in Glioblastoma Causes a Robust Switch in Cell Fate Resulting in Tumor Progression.

Cell reports

Nienke A de Vries, Danielle Hulsman, Waseem Akhtar, Johann de Jong, Denise C Miles, Marleen Blom, Olaf van Tellingen, Jos Jonkers, Maarten van Lohuizen

Affiliations

  1. Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
  2. Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
  3. Division of Clinical Chemistry/Preclinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
  4. Division of Molecular Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
  5. Division of Molecular Genetics, Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. Electronic address: [email protected].

PMID: 25600873 DOI: 10.1016/j.celrep.2014.12.028

Abstract

EZH2 is frequently overexpressed in glioblastoma (GBM), suggesting an oncogenic function that could be a target for therapeutic intervention. However, reduced EZH2 activity can also promote tumorigenesis, leading to concerns about the use of EZH2 inhibitors. Here, we provide further insight about the effects of prolonged Ezh2 inhibition in glioblastoma using preclinical mouse models and primary tumor-derived human GBM cell lines. Using doxycycline-inducible shRNAs that mimic the effects of a selective EZH2 inhibitor, we demonstrate that prolonged Ezh2 depletion causes a robust switch in cell fate, including significantly enhanced proliferation, DNA damage repair, and activation of part of the pluripotency network, resulting in altered tumor cell identity and tumor progression. Short-term Ezh2 depletion significantly improved survival without the tumor progression observed upon prolonged Ezh2 depletion, suggesting that precise dosing regiments are very important. These results could be of high clinical relevance with regard to how glioblastomas should be treated with epigenetic therapies.

Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

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