Details

Autor(en) / Beteiligte

• Jin, Xun
• Kim, Leo J Y
• Wu, Qiulian
• Wallace, Lisa C
• Prager, Briana C
• Sanvoranart, Tanwarat
• Gimple, Ryan C
• Wang, Xiuxing
• Mack, Stephen C
• Miller, Tyler E
• Huang, Ping
• Valentim, Claudia L
• Zhou, Qi-Gang
• Barnholtz-Sloan, Jill S
• Bao, Shideng
• Sloan, Andrew E
• Rich, Jeremy N

Titel

Targeting glioma stem cells through combined BMI1 and EZH2 inhibition

Ist Teil von

• Nature medicine, 2017-11, Vol.23 (11), p.1352-1361

Ort / Verlag

United States: Nature Publishing Group

Erscheinungsjahr

2017

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Glioblastomas are lethal cancers defined by angiogenesis and pseudopalisading necrosis. Here, we demonstrate that these histological features are associated with distinct transcriptional programs, with vascular regions showing a proneural profile, and hypoxic regions showing a mesenchymal pattern. As these regions harbor glioma stem cells (GSCs), we investigated the epigenetic regulation of these two niches. Proneural, perivascular GSCs activated EZH2, whereas mesenchymal GSCs in hypoxic regions expressed BMI1 protein, which promoted cellular survival under stress due to downregulation of the E3 ligase RNF144A. Using both genetic and pharmacologic inhibition, we found that proneural GSCs are preferentially sensitive to EZH2 disruption, whereas mesenchymal GSCs are more sensitive to BMI1 inhibition. Given that glioblastomas contain both proneural and mesenchymal GSCs, combined EZH2 and BMI1 targeting proved more effective than either agent alone both in culture and in vivo, suggesting that strategies that simultaneously target multiple epigenetic regulators within glioblastomas may be effective in overcoming therapy resistance caused by intratumoral heterogeneity.