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Nat Med. 2017 Nov;23(11):1352-1361. doi: 10.1038/nm.4415. Epub 2017 Oct 9.

Targeting glioma stem cells through combined BMI1 and EZH2 inhibition.

Jin X1,2,3, Kim LJY1,4,5,6, Wu Q1,6, Wallace LC1, Prager BC1,4,5,6,7, Sanvoranart T1, Gimple RC1,4,5,6, Wang X1,6, Mack SC1,8, Miller TE1,4,5, Huang P1, Valentim CL1, Zhou QG1, Barnholtz-Sloan JS9, Bao S1,7,9, Sloan AE9,10, Rich JN1,6,7,9.

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Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Tianjin Medical University Cancer Institute and Hospital, Tianjin, P.R. China.
First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, P.R. China.
Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
Medical Scientist Training Program, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
Division of Regenerative Medicine, Department of Medicine, University of San Diego, San Diego, California, USA.
Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA.
Department of Pediatrics, Division of Pediatric Hematology and Oncology, Baylor College of Medicine, Houston, Texas, USA.
Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
Department of Neurological Surgery, University Hospitals-Cleveland Medical Center, Cleveland, Ohio, USA.


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.

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