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Author Notes:

orrespondence to:Vidya Gopalakrishnan, Email: vgopalak@mdanderson.org

Author contributions: SS, BK and SM were involved in conceptualization and performance of in vitro and in vivo experiments, data analysis and generation of manuscript.

KS, YY and KC were involved in experimental design, execution of experiments and analyses.

RL, SG, JN, VR, JF & VG were involved in study supervision, experimental design, data analysis, review of pathology, and writing of manuscript.

The authors thank Dr. Michelle Monje, Stanford University, Stanford, CA for providing human SU-DIPG cell lines.

The authors declare no conflicts of interest.

Subjects:

Research Funding:

This work was supported by grants from the National Institutes of Health (NIH-Grant# 5R01-NS-079715-01) to VG and Hyundai Hope on Wheels Research Award to JF and VG.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Oncology
  • Cell Biology
  • DIPG
  • REST
  • vasculature
  • gremlin
  • VEGFR2
  • ENDOTHELIAL GROWTH-FACTOR
  • GLIOBLASTOMA STEM-CELLS
  • RESTRICTIVE SILENCER FACTOR
  • BONE MORPHOGENETIC PROTEIN
  • ACTIVATING ACVR1 MUTATIONS
  • HIGH-GRADE GLIOMAS
  • PEDIATRIC GLIOMAS
  • NEURONAL GENES
  • BRAIN-TUMORS
  • ONCOGENIC PROPERTIES

REST upregulates gremlin to modulate diffuse intrinsic pontine glioma vasculature

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Journal Title:

Oncotarget

Volume:

Volume 9, Number 4

Publisher:

, Pages 5233-5250

Type of Work:

Article | Final Publisher PDF

Abstract:

Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive glial tumor that occurs in children. The extremely poor median and 5-year survival in children afflicted with DIPG highlights the need for novel biology-driven therapeutics. Here, we have implicated the chromatin remodeler and regulator of brain development called RE1 Silencing Transcription Factor (REST), in DIPG pathology. We show that REST protein is aberrantly elevated in at least 21% of DIPG tumors compared to normal controls. Its knockdown in DIPG cell lines diminished cell growth and decreased their tumorigenicity in mouse intracranial models. DIPGs are vascularized tumors and interestingly, REST loss in DIPG cells also caused a substantial decline in tumor vasculature as measured by a decrease in CD31 and VEGFR2 staining. These observations were validated in vitro, where a significant decline in tube formation by human umbilical vein endothelial cells (HUVEC) was seen following REST-loss in DIPG cells. Mechanistically, REST controlled the secretion of a pro-angiogenic molecule and ligand for VEGFR2 called Gremlin-1 (GREM-1), and was associated with enhanced AKT activation. Importantly, the decline in tube formation caused by REST loss could be rescued by addition of recombinant GREM-1, which also caused AKT activation in HUVECs and human brain microvascular endothelial cells (HBMECs). In summary, our study is the first to demonstrate autocrine and paracrine functions for REST in DIPG development. It also provides the foundation for future investigations on antiangiogenic therapies targeting GREM-1 in combination with drugs that target RESTassociated chromatin remodeling activities.

Copyright information:

© Shaik et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 3.0 Unported License (http://creativecommons.org/licenses/by/3.0/).

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