REST promotes ETS1‐dependent vascular growth in medulloblastoma. Issue 5 (7th February 2021)

• Record Type: Journal Article
• Authors: Shaik, Shavali; Maegawa, Shinji; Haltom, Amanda R; Wang, Feng; Xiao, Xue; Dobson, Tara; Sharma, Ajay; Yang, Yanwen; Swaminathan, Jyothishmathi; Kundra, Vikas; Li, Xiao Nan; Schadler, Keri; Harmanci, Arif; Xu, Lin; Gopalakrishnan, Vidya
• Is Part Of: Molecular oncology. Volume 15:Issue 5(2021)
• Page Start: 1486
• Page End: 1506
• Publication Date: 2021-02-07
• Subjects: medulloblastoma -- REST -- NRSF -- tumor microenvironment -- vasculature; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1002/1878-0261.12903
• Languages: English
• ISSNs: 1574-7891

Abstract

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 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. Abstract : Expression of REST, a negative regulator of neurogenesis, is aberrantly elevated in SHH medulloblastomas and contributes to tumor progression through upregulation of hedgehog signaling and cell proliferative pathways. Here, we identify a role for REST in vascular remodeling. REST elevation increased secretion of proangiogenic factors and upregulated genes with potential to drive an endothelial cell‐like phenotype in tumor cells.