Open AccessREST promotes ETS1‐dependent vascular growth in medulloblastoma
Author(s) -
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
Publication year - 2021
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12903
Subject(s) - biology , paracrine signalling , autocrine signalling , cancer research , transcription factor , gene silencing , microbiology and biotechnology , neurogenesis , receptor , gene , genetics
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.