Chromodomain Helicase DNA-Binding Protein 7 Is Suppressed in the Perinecrotic/Ischemic Microenvironment and Is a Novel Regulator of Glioblastoma Angiogenesis

• Authors: Nathaniel H. Boyd, University of Alabama Birmingham; Kiera Walker, University of Alabama Birmingham; Adetokunbo Ayokanmbi, University of Alabama Birmingham; Emily R. Gordon, HudsonAlpha Institute for Biotechnology; Julia Whetsel, University of Alabama Birmingham; Cynthia M. Smith, University of Alabama Birmingham; Richard G. Sanchez, University of Alabama Birmingham; Farah Lubin, University of Alabama Birmingham; Asmi Chakraborty, University of Alabama Birmingham; Nhat Tran Anh, University of Alabama Birmingham; Cameron Herting, Emory University; Dolores Hambardzumyan, Emory University; G. Yancey Gillespie, University of Alabama Birmingham; James R. Hackney, University of Alabama Birmingham; Sara J. Cooper, HudsonAlpha Institute for Biotechnology; Kai Jiao, University of Alabama Birmingham; Anita B. Hjelmeland, University of Alabama Birmingham
• Journal Title: Stem Cells
• Volume: Volume 37, Number 4
• Publisher: Wiley | 2019-04-01, Pages 453-462
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1002/stem.2969
• Subjects: Health Sciences, Oncology; Biology, Cell; Engineering, Biomedical; Biology, Genetics
• Keywords: Science & Technology; Life Sciences & Biomedicine; Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology; CHD7; Ischemia; Glioblastoma; Tumor initiating cell; Cancer stem cell; Tumor microenvironment; Hypoxia; Hypoxia inducible factors; Glioma stem cells; Expression; Tumors; Epigenetics; Prognosis; Survival; Reveals; YKL-40

Abstract

Tumorigenic and non-neoplastic tissue injury occurs via the ischemic microenvironment defined by low oxygen, pH, and nutrients due to blood supply malfunction. Ischemic conditions exist within regions of pseudopalisading necrosis, a pathological hallmark of glioblastoma (GBM), the most common primary malignant brain tumor in adults. To recapitulate the physiologic microenvironment found in GBM tumors and tissue injury, we developed an in vitro ischemic model and identified chromodomain helicase DNA-binding protein 7 (CHD7) as a novel ischemia-regulated gene. Point mutations in the CHD7 gene are causal in CHARGE syndrome (a developmental disorder causing coloboma, heart defects, atresia choanae, retardation of growth, and genital and ear anomalies) and interrupt the epigenetic functions of CHD7 in regulating neural stem cell maintenance and development. Using our ischemic system, we observed microenvironment-mediated decreases in CHD7 expression in brain tumor-initiating cells and neural stem cells. Validating our approach, CHD7 was suppressed in the perinecrotic niche of GBM patient and xenograft sections, and an interrogation of patient gene expression datasets determined correlations of low CHD7 with increasing glioma grade and worse patient outcomes. Segregation of GBM by molecular subtype revealed a novel observation that CHD7 expression is elevated in proneural versus mesenchymal GBM. Genetic targeting of CHD7 and subsequent gene ontology analysis of RNA sequencing data indicated angiogenesis as a primary biological function affected by CHD7 expression changes. We validated this finding in tube-formation assays and vessel formation in orthotopic GBM models. Together, our data provide further understanding of molecular responses to ischemia and a novel function of CHD7 in regulating angiogenesis in both neoplastic and non-neoplastic systems. Stem Cells 2019;37:453–462.