REST promotes ETS1-dependent vascular growth in medulloblastoma.

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.

• Authors: 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
• Journal: Molecular oncology (Mol Oncol) Vol. 15 Issue 5 Pg. 1486-1506 (05 2021) ISSN: 1878-0261 [Electronic] United States
• PMID: 33469989 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

Chemical References

• ETS1 protein, human
• Proto-Oncogene Protein c-ets-1
• RE1-silencing transcription factor
• Repressor Proteins

Topics

• Animals
• Cell Proliferation (genetics)
• Cells, Cultured
• Cerebellar Neoplasms (blood supply, genetics, pathology)
• Human Umbilical Vein Endothelial Cells
• Humans
• Medulloblastoma (blood supply, genetics, pathology)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Mice, Transgenic
• Neovascularization, Pathologic (genetics, pathology)
• Proto-Oncogene Protein c-ets-1 (physiology)
• Repressor Proteins (physiology)
• Tumor Microenvironment (genetics)