REST promotes ETS1‐dependent vascular growth in medulloblastoma

Autor: 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
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Molecular Oncology, Vol 15, Iss 5, Pp 1486-1506 (2021)
Druh dokumentu: article
ISSN: 1878-0261
1574-7891
DOI: 10.1002/1878-0261.12903
Popis: 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.
Databáze: Directory of Open Access Journals
Externí odkaz: