REST promotes ETS1-dependent vascular growth in medulloblastoma

Shavali Shaik, Shinji Maegawa, Amanda R. Haltom, Feng Wang, Xue Xiao, Tara Dobson, Ajay Sharma, Yanwen Yang, Jyothishmathi Swaminathan, Vikas Kundra, Xiao Nan Li, Keri Schadler, Arif Harmanci, Lin Xu, Vidya Gopalakrishnan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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 RESTTG 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.

Original languageEnglish (US)
Pages (from-to)1486-1506
Number of pages21
JournalMolecular oncology
Volume15
Issue number5
DOIs
StatePublished - May 2021

Keywords

  • NRSF
  • REST
  • medulloblastoma
  • tumor microenvironment
  • vasculature

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Oncology
  • Cancer Research

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