REST upregulates gremlin to modulate diffuse intrinsic pontine glioma vasculature

• Type of Material: Article
• Authors: Shavali Shaik, University of Texas; Bridget Kennis, University of Texas; Shinji Maegawa, University of Texas; Keri Schadler, University of Texas; Yang Yang, University of Texas; Keri Callegari, University of Texas; Rishi R. Lulla, Northwestern University; Stewart Goldman, Northwestern University; Javad Nazarian, George Washington University; Veena Rajaram, University of Texas Southwestern Medical Center; Jason Fangusaro, Emory University; Vidya Gopalakrishnan, University of Texas
• Language: English
• Date: 2018-01-12
• Publisher: Impact Journals
• Publication Version: Final Published Version
• Copyright Statement: © Shaik et al.
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.18632/oncotarget.23750
• Title of Journal or Parent Work: Oncotarget
• ISSN: 1949-2553
• Volume: 9
• Issue: 4
• Start Page: 5233
• End Page: 5250
• Grant/Funding Information: 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: DIPG; gremlin; NEURONAL GENES; BRAIN-TUMORS; REST; Cell Biology; GLIOBLASTOMA STEM-CELLS; PEDIATRIC GLIOMAS; RESTRICTIVE SILENCER FACTOR; Oncology; HIGH-GRADE GLIOMAS; BONE MORPHOGENETIC PROTEIN; ACTIVATING ACVR1 MUTATIONS; ENDOTHELIAL GROWTH-FACTOR; vasculature; Life Sciences & Biomedicine; ONCOGENIC PROPERTIES; VEGFR2; Science & Technology
• Research Categories: Health Sciences, Oncology; Biology, Cell

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.