Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Cell reports (Cambridge), 2015-01, Vol.10 (3), p.383-397

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2015

Quelle

Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals

Beschreibungen/Notizen

• 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. [Display omitted] •Robust switch in cell fate upon prolonged Ezh2 depletion causes tumor progression•Ezh2 depletion results in modified differentiation status and tumor cell identity•Prolonged Ezh2 depletion in glioblastoma significantly enhances DNA damage repair•Effects of EZH2 inhibition in glioblastoma depend on well-balanced drug dosing EZH2 is reported to have both oncogenic and tumorsuppressor functions, leading to concerns about the use of EZH2 inhibitors. de Vries et al. show that prolonged Ezh2 inhibition in glioblastoma results in an altered tumor cell identity and tumor progression, unlike short-term Ezh2 inhibition, suggesting that well-balanced drug dosing is important.