CHD7 is Suppressed in the Perinecrotic/Ischemic Microenvironment and is a Novel Regulator of Glioblastoma Angiogenesis

The ischemic microenvironment in both tumor and non ‐neoplastic tissue can drive new blood vessel formation to adapt to changes in pH, oxygen tension, and restricted nutrient availability. Using neural progenitor and glioblastoma cells in an in vitro ischemic model, we demonstrated that mRNA and protein expression of the epigenetic reader CHD7 was suppressed in the ischemic microenvironment. Reducing CHD7 altered the transcriptome to increase angiogenesis‐related pathways that include CHI3L1 (YKL‐40) and increased measures of angiogenesis in vitro and in vivo. ABSTRACTTumorigenic 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 CHA RGE syndrome, a CNS developmental disorder, 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 cel...
Source: Stem Cells - Category: Stem Cells Authors: Tags: Cancer Stem Cells Source Type: research