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A GATA4-regulated tumor suppressor network represses formation of malignant human astrocytomas

Glioblastoma Multiforme (GBM), the most common and lethal primary human brain tumor, exhibits multiple molecular aberrations. We report that loss of the transcription factor GATA4, a negative regulator of normal astrocyte proliferation, is a driver in glioma formation and fulfills the hallmarks of a...

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Autores principales: Agnihotri, Sameer, Wolf, Amparo, Munoz, Diana M., Smith, Christopher J., Gajadhar, Aaron, Restrepo, Andres, Clarke, Ian D., Fuller, Gregory N., Kesari, Santosh, Dirks, Peter B., McGlade, C. Jane, Stanford, William L., Aldape, Kenneth, Mischel, Paul S., Hawkins, Cynthia, Guha, Abhijit
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3135351/
https://www.ncbi.nlm.nih.gov/pubmed/21464220
http://dx.doi.org/10.1084/jem.20102099
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author Agnihotri, Sameer
Wolf, Amparo
Munoz, Diana M.
Smith, Christopher J.
Gajadhar, Aaron
Restrepo, Andres
Clarke, Ian D.
Fuller, Gregory N.
Kesari, Santosh
Dirks, Peter B.
McGlade, C. Jane
Stanford, William L.
Aldape, Kenneth
Mischel, Paul S.
Hawkins, Cynthia
Guha, Abhijit
author_facet Agnihotri, Sameer
Wolf, Amparo
Munoz, Diana M.
Smith, Christopher J.
Gajadhar, Aaron
Restrepo, Andres
Clarke, Ian D.
Fuller, Gregory N.
Kesari, Santosh
Dirks, Peter B.
McGlade, C. Jane
Stanford, William L.
Aldape, Kenneth
Mischel, Paul S.
Hawkins, Cynthia
Guha, Abhijit
author_sort Agnihotri, Sameer
collection PubMed
description Glioblastoma Multiforme (GBM), the most common and lethal primary human brain tumor, exhibits multiple molecular aberrations. We report that loss of the transcription factor GATA4, a negative regulator of normal astrocyte proliferation, is a driver in glioma formation and fulfills the hallmarks of a tumor suppressor gene (TSG). Although GATA4 was expressed in normal brain, loss of GATA4 was observed in 94/163 GBM operative samples and was a negative survival prognostic marker. GATA4 loss occurred through promoter hypermethylation or novel somatic mutations. Loss of GATA4 in normal human astrocytes promoted high-grade astrocytoma formation, in cooperation with other relevant genetic alterations such as activated Ras or loss of TP53. Loss of GATA4 with activated Ras in normal astrocytes promoted a progenitor-like phenotype, formation of neurospheres, and the ability to differentiate into astrocytes, neurons, and oligodendrocytes. Re-expression of GATA4 in human GBM cell lines, primary cultures, and brain tumor–initiating cells suppressed tumor growth in vitro and in vivo through direct activation of the cell cycle inhibitor P21(CIP1), independent of TP53. Re-expression of GATA4 also conferred sensitivity of GBM cells to temozolomide, a DNA alkylating agent currently used in GBM therapy. This sensitivity was independent of MGMT (O-6-methylguanine-DNA-methyltransferase), the DNA repair enzyme which is often implicated in temozolomide resistance. Instead, GATA4 reduced expression of APNG (alkylpurine-DNA-N-glycosylase), a DNA repair enzyme which is poorly characterized in GBM-mediated temozolomide resistance. Identification and validation of GATA4 as a TSG and its downstream targets in GBM may yield promising novel therapeutic strategies.
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spelling pubmed-31353512011-10-11 A GATA4-regulated tumor suppressor network represses formation of malignant human astrocytomas Agnihotri, Sameer Wolf, Amparo Munoz, Diana M. Smith, Christopher J. Gajadhar, Aaron Restrepo, Andres Clarke, Ian D. Fuller, Gregory N. Kesari, Santosh Dirks, Peter B. McGlade, C. Jane Stanford, William L. Aldape, Kenneth Mischel, Paul S. Hawkins, Cynthia Guha, Abhijit J Exp Med Article Glioblastoma Multiforme (GBM), the most common and lethal primary human brain tumor, exhibits multiple molecular aberrations. We report that loss of the transcription factor GATA4, a negative regulator of normal astrocyte proliferation, is a driver in glioma formation and fulfills the hallmarks of a tumor suppressor gene (TSG). Although GATA4 was expressed in normal brain, loss of GATA4 was observed in 94/163 GBM operative samples and was a negative survival prognostic marker. GATA4 loss occurred through promoter hypermethylation or novel somatic mutations. Loss of GATA4 in normal human astrocytes promoted high-grade astrocytoma formation, in cooperation with other relevant genetic alterations such as activated Ras or loss of TP53. Loss of GATA4 with activated Ras in normal astrocytes promoted a progenitor-like phenotype, formation of neurospheres, and the ability to differentiate into astrocytes, neurons, and oligodendrocytes. Re-expression of GATA4 in human GBM cell lines, primary cultures, and brain tumor–initiating cells suppressed tumor growth in vitro and in vivo through direct activation of the cell cycle inhibitor P21(CIP1), independent of TP53. Re-expression of GATA4 also conferred sensitivity of GBM cells to temozolomide, a DNA alkylating agent currently used in GBM therapy. This sensitivity was independent of MGMT (O-6-methylguanine-DNA-methyltransferase), the DNA repair enzyme which is often implicated in temozolomide resistance. Instead, GATA4 reduced expression of APNG (alkylpurine-DNA-N-glycosylase), a DNA repair enzyme which is poorly characterized in GBM-mediated temozolomide resistance. Identification and validation of GATA4 as a TSG and its downstream targets in GBM may yield promising novel therapeutic strategies. The Rockefeller University Press 2011-04-11 /pmc/articles/PMC3135351/ /pubmed/21464220 http://dx.doi.org/10.1084/jem.20102099 Text en © 2011 Agnihotri et al. https://creativecommons.org/licenses/by-nc-sa/3.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ (https://creativecommons.org/licenses/by-nc-sa/3.0/) ).
spellingShingle Article
Agnihotri, Sameer
Wolf, Amparo
Munoz, Diana M.
Smith, Christopher J.
Gajadhar, Aaron
Restrepo, Andres
Clarke, Ian D.
Fuller, Gregory N.
Kesari, Santosh
Dirks, Peter B.
McGlade, C. Jane
Stanford, William L.
Aldape, Kenneth
Mischel, Paul S.
Hawkins, Cynthia
Guha, Abhijit
A GATA4-regulated tumor suppressor network represses formation of malignant human astrocytomas
title A GATA4-regulated tumor suppressor network represses formation of malignant human astrocytomas
title_full A GATA4-regulated tumor suppressor network represses formation of malignant human astrocytomas
title_fullStr A GATA4-regulated tumor suppressor network represses formation of malignant human astrocytomas
title_full_unstemmed A GATA4-regulated tumor suppressor network represses formation of malignant human astrocytomas
title_short A GATA4-regulated tumor suppressor network represses formation of malignant human astrocytomas
title_sort gata4-regulated tumor suppressor network represses formation of malignant human astrocytomas
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3135351/
https://www.ncbi.nlm.nih.gov/pubmed/21464220
http://dx.doi.org/10.1084/jem.20102099
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