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Cleveland Clinic, Tianjin Medical University Cancer Institute and Hospital, First Affiliated Hospital of Wenzhou Medical University
Nat. Med., Published online 09 October 2017 | doi:10.1038/nm.4415
Targeting glioma stem cells through combined BMI1 and EZH2 inhibition
Xun Jin1-3, Leo J Y Kim1,4-6, Qiulian Wu1,6, Lisa C Wallace1, Briana C Prager1,4-7, Tanwarat Sanvoranart1, Ryan C Gimple1,4-6, Xiuxing Wang1,6, Stephen C Mack1,8, Tyler E Miller1,4,5, Ping Huang1, Claudia L Valentim1, Qi-gang Zhou1, Jill S Barnholtz-Sloan9, Shideng Bao1,7,9, Andrew E Sloan9,10 & Jeremy N Rich1,6,7,9
1Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA. 2Tianjin Medical University Cancer Institute and Hospital, Tianjin, P.R. China. 3First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, P.R. China. 4Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA. 5Medical Scientist Training Program, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA. 6Division of Regenerative Medicine, Department of Medicine, University of San Diego, San Diego, California, USA. 7Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA. 8Department of Pediatrics, Division of Pediatric Hematology and Oncology, Baylor College of Medicine, Houston, Texas, USA. 9Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. 10Department of Neurological Surgery, University Hospitals?Cleveland Medical Center, Cleveland, Ohio, USA.
Correspondence to: Jeremy N Rich or Andrew E Sloan
1Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA. 2Tianjin Medical University Cancer Institute and Hospital, Tianjin, P.R. China. 3First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, P.R. China. 4Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA. 5Medical Scientist Training Program, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA. 6Division of Regenerative Medicine, Department of Medicine, University of San Diego, San Diego, California, USA. 7Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA. 8Department of Pediatrics, Division of Pediatric Hematology and Oncology, Baylor College of Medicine, Houston, Texas, USA. 9Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. 10Department of Neurological Surgery, University Hospitals?Cleveland Medical Center, Cleveland, Ohio, USA.
Correspondence to: Jeremy N Rich or Andrew E Sloan
Abstract
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.
논문정보
- Research article
- 2017년 10월 (BRIC 등록일 2017-11-07)
- 국외 연구진
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