REST promotes ETS1-dependent vascular growth in medulloblastoma.

Autor: Shaik S; Department of Pediatrics, University of Texas, MD Anderson Cancer Center, Houston, TX, USA., Maegawa S; Department of Pediatrics, University of Texas, MD Anderson Cancer Center, Houston, TX, USA., Haltom AR; Department of Pediatrics, University of Texas, MD Anderson Cancer Center, Houston, TX, USA., Wang F; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Department of Population & Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA., Xiao X; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Department of Population & Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA., Dobson T; Department of Pediatrics, University of Texas, MD Anderson Cancer Center, Houston, TX, USA., Sharma A; Department of Pediatrics, University of Texas, MD Anderson Cancer Center, Houston, TX, USA., Yang Y; Department of Pediatrics, University of Texas, MD Anderson Cancer Center, Houston, TX, USA., Swaminathan J; Department of Pediatrics, University of Texas, MD Anderson Cancer Center, Houston, TX, USA., Kundra V; Departments of Abdominal Imaging and Cancer Systems, University of Texas, MD Anderson Cancer Center, Houston, TX, USA., Li XN; Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA., Schadler K; Department of Pediatrics, University of Texas, MD Anderson Cancer Center, Houston, TX, USA., Harmanci A; Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center, Houston, TX, USA., Xu L; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Department of Population & Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA., Gopalakrishnan V; Department of Pediatrics, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.; Department of Molecular and Cellular Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.; Center for Cancer Epigenetics, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.; Brain Tumor Center, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
Jazyk: angličtina
Zdroj: Molecular oncology [Mol Oncol] 2021 May; Vol. 15 (5), pp. 1486-1506. Date of Electronic Publication: 2021 Feb 07.
DOI: 10.1002/1878-0261.12903
Abstrakt: Expression of the RE1-silencing transcription factor (REST), a master regulator of neurogenesis, is elevated in medulloblastoma (MB) tumors. A cell-intrinsic function for REST in MB tumorigenesis is known. However, a role for REST in the regulation of MB tumor microenvironment has not been investigated. Here, we implicate REST in remodeling of the MB vasculature and describe underlying mechanisms. Using REST TG mice, we demonstrate that elevated REST expression in cerebellar granule cell progenitors, the cells of origin of sonic hedgehog (SHH) MBs, increased vascular growth. This was recapitulated in MB xenograft models and validated by transcriptomic analyses of human MB samples. REST upregulation was associated with enhanced secretion of proangiogenic factors. Surprisingly, a REST-dependent increase in the expression of the proangiogenic transcription factor E26 oncogene homolog 1, and its target gene encoding the vascular endothelial growth factor receptor-1, was observed in MB cells, which coincided with their localization at the tumor vasculature. These observations were confirmed by RNA-Seq and microarray analyses of MB cells and SHH-MB tumors. Thus, our data suggest that REST elevation promotes vascular growth by autocrine and paracrine mechanisms.
(© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
Databáze: MEDLINE
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