REST promotes ETS1‐dependent vascular growth in medulloblastoma
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 investiga...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2021-05-01
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| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.12903 |
| _version_ | 1819295654112919552 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Shavali Shaik |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-24T04:45:39Z |
| format | Article |
| id | doaj.art-2fd985365fb74e1ca2c9a58c50c1a78b |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-12-24T04:45:39Z |
| publishDate | 2021-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-2fd985365fb74e1ca2c9a58c50c1a78b2022-12-21T17:14:42ZengWileyMolecular Oncology1574-78911878-02612021-05-011551486150610.1002/1878-0261.12903REST promotes ETS1‐dependent vascular growth in medulloblastomaShavali Shaik0Shinji Maegawa1Amanda R Haltom2Feng Wang3Xue Xiao4Tara Dobson5Ajay Sharma6Yanwen Yang7Jyothishmathi Swaminathan8Vikas Kundra9Xiao Nan Li10Keri Schadler11Arif Harmanci12Lin Xu13Vidya Gopalakrishnan14Department of Pediatrics University of Texas, MD Anderson Cancer Center Houston TX USADepartment of Pediatrics University of Texas, MD Anderson Cancer Center Houston TX USADepartment of Pediatrics University of Texas, MD Anderson Cancer Center Houston TX USADepartment of Pediatrics University of Texas Southwestern Medical Center Dallas TX USADepartment of Pediatrics University of Texas Southwestern Medical Center Dallas TX USADepartment of Pediatrics University of Texas, MD Anderson Cancer Center Houston TX USADepartment of Pediatrics University of Texas, MD Anderson Cancer Center Houston TX USADepartment of Pediatrics University of Texas, MD Anderson Cancer Center Houston TX USADepartment of Pediatrics University of Texas, MD Anderson Cancer Center Houston TX USADepartments of Abdominal Imaging and Cancer Systems University of TexasMD Anderson Cancer Center Houston TX USADepartment of Pediatrics Northwestern University Feinberg School of Medicine Chicago IL USADepartment of Pediatrics University of Texas, MD Anderson Cancer Center Houston TX USACenter for Precision Health School of Biomedical Informatics The University of Texas Health Science Center Houston TX USADepartment of Pediatrics University of Texas Southwestern Medical Center Dallas TX USADepartment of Pediatrics University of Texas, MD Anderson Cancer Center Houston TX USAExpression 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.https://doi.org/10.1002/1878-0261.12903medulloblastomaRESTNRSFtumor microenvironmentvasculature |
| spellingShingle | 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 REST promotes ETS1‐dependent vascular growth in medulloblastoma Molecular Oncology medulloblastoma REST NRSF tumor microenvironment vasculature |
| title | REST promotes ETS1‐dependent vascular growth in medulloblastoma |
| title_full | REST promotes ETS1‐dependent vascular growth in medulloblastoma |
| title_fullStr | REST promotes ETS1‐dependent vascular growth in medulloblastoma |
| title_full_unstemmed | REST promotes ETS1‐dependent vascular growth in medulloblastoma |
| title_short | REST promotes ETS1‐dependent vascular growth in medulloblastoma |
| title_sort | rest promotes ets1 dependent vascular growth in medulloblastoma |
| topic | medulloblastoma REST NRSF tumor microenvironment vasculature |
| url | https://doi.org/10.1002/1878-0261.12903 |
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